JP2022529379A - Prostate-specific membrane antigen (PSMA) inhibitor as a diagnostic and radionuclide therapeutic agent - Google Patents

Abstract

The present disclosure relates to compounds of formula I. These compounds show very good binding affinity for the PSMA binding site. They contain a chelated moiety that can be labeled with a radioisotope or a radiometal such as [68Ga] or [177Lu]. The present disclosure also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula I or a complex thereof, or a pharmaceutically acceptable salt thereof. The present disclosure relates to methods of imaging a subject, including administering to the subject the radiolabeled compound disclosed herein; and obtaining an image of the subject or a portion of the subject.

Description

Field of Invention The present invention is an invention in the field of radionuclide imaging and therapeutic agents. In particular, derivatives of urea-based prostate-specific membrane antigen (PSMA) inhibitors, including derivatives with chelated moieties capable of chelating radioactive metals and derivatives with halogenated labeled phenyl, are disclosed. Will be done.

Background of the Invention Prostate-specific membrane antigen (PSMA) is a very specific prostate epithelial cell membrane antigen. Its natural substrates are N-acetyl-aspartyl glutamate and foryl-poly-γ-glutamate (prostate-related PSMA) (Scheme 1).

PSMA is highly expressed in a variety of tumors, including prostate cancer. Often, PSMA expression is increased in high-grade cancers and metastatic diseases. High expression of PSMA is seen in the overwhelming majority of angiogenesis in solid tumors, but not in the normal vasculature. This makes PSMA a suitable target for cancer detection and treatment.

Several small molecule-based PSMA contrast agents have been reported in the literature. 2 [(3-Amino-3-carboxypropyl) (hydroxy) (phosphinyl) -methyl] pentane-1,5-diacid (GPI), 2- (3-mercaptopropyl) pentane-diacid (2-PMPA) , Phosphoramidates, in particular urea-Glu groups (Glu-NH-CO-NH-Lys (Ahx)) (Scheme 2), various PSMA target core structures have been used. See, for example, US2004054190; Kozikowski AP, et al., J. Med. Chem. 47: 1729-38 (2004). Based on these bound core structures, many PSMA inhibitors have been reported to be highly selective and potent. After labeling with various isotopes, they have been disclosed to be useful in in vivo imaging (SPECT or PET) and in radionuclide therapy.

SPECT contrast agents: urea-based ligand systems including [ ¹²³ I] MIP-1072, [ ¹²³ I] MIP-1095, [ ^{99 m} Tc] MIP-1404, and [ ^{99 m} Tc] Tc-MIP-1405 (Scheme 3). Several potential PSMA-targeted contrast agents using Glu-NH-CO-NH or Glu-NH-CO-NH-Lys (Ahx) have entered clinical trials. The results of Phase II clinical studies suggest that these SPECT PSMA contrast agents are suitable for the diagnosis of the prostate and other related solid tumors.

An ^18F -labeled PET contrast agent targeting PSMA has also been reported (Scheme 4).

Over the last two decades, there have been numerous reports on the use of ⁶⁸ Ga-labeled small molecules and peptides for imaging various tumors. Among them, [ ⁶⁸ Ga] DOTA-TOC, [ ⁶⁸ Ga] DOTA-TATE, and [ ⁶⁸ Ga] DOTA-NOC are agents for detecting neuroendocrine tumors (NETs) expressing somatostatin receptors. Used. The ⁶⁸ Ga-labeled compound [ ⁶⁸ Ga] PSMA-11 has been well studied (Scheme 4). Clinical data were generated and they demonstrated the ability to detect and monitor prostate cancer [4]. Additional ⁶⁸ Ga-labeled compounds targeting PSMA binding, including ⁶⁸ Ga PSMA-093, have been reported (Scheme 4), which have been reported to have improved tumor targeting properties and pharmacokinetics [5]. See U.S. Patent Application Publication No. 2016/0228587.

治療用の１つのその他の放射性核種は^１３１Ｉであり、これは８．０２日の物理的半減期で電子を放出し（ベータ放射線）、最大ベータエネルギー６０６ｋｅＶ（８９％存在度）および３６４ｋｅＶのガンマ線（８１％存在度）を放出する。甲状腺がんを処置するために^１３１Ｉヨウ化物を使用する、長い歴史がある。これは甲状腺患者の標準的なケアである。^１３１Ｉ標識ＭＩＰ－１０９５（スキーム３）は高いＰＳＭＡ結合親和性（Ｋｉ＝４．６ｎＭ）を示し、魅力ある代替ＰＳＭＡ標的放射性核種治療剤であることが、報告されている［１］。既に、リンカー領域に構造修飾を持ついくつかの放射性ヨウ素化撮像および治療剤は、改善された腫瘍標的特性および薬物動態を有することが報告されている。米国特許出願公開第２０１６／０２２８５８７号を参照されたい。
ｉｎ ｖｉｖｏ撮像および放射性核種療法でのＰＳＭＡ阻害剤として、Ｇｌｕ－ＮＨ－ＣＯ－ＮＨ－Ｌｙｓ誘導体をさらに改善する必要性が、依然として存在する。 Based on targeting overexpressed PSMA binding sites in most prostate cancer patients, ¹⁷⁷ Lu-labeled PSMA-617 and DOTAGA- (yl) -fk (sub-KuE) (PSMA-I & T) are PSMA. It was reported to be targeted radionuclide therapy (Scheme 5) (see Discussion [10-13] [14] [15]). The results of clinical trials for [ ¹⁷⁷ Lu] PSMA 617 [16] and [ ¹⁷⁷ Lu] PSMA I & T [17] (Scheme 5) were promising.

Another therapeutic radionuclide is ¹³¹ I, which emits electrons with a physical half-life of 8.02 days (beta radiation), with a maximum beta energy of 606 keV (89% abundance) and 364 keV gamma rays. Releases (81% abundance). There is a long history of using ¹³¹ I iodide to treat thyroid cancer. This is standard care for thyroid patients. ¹³¹ I-labeled MIP-1095 (Scheme 3) exhibits high PSMA binding affinity (Ki = 4.6 nM) and has been reported to be an attractive alternative PSMA-targeted radionuclide therapeutic agent [1]. It has already been reported that some radioiodinated imaging and therapeutic agents with structural modifications in the linker region have improved tumor targeting properties and pharmacokinetics. See U.S. Patent Application Publication No. 2016/0228587.
There is still a need to further improve the Glu-NH-CO-NH-Lys derivative as a PSMA inhibitor in in vivo imaging and radionuclide therapy.

US Patent Application Publication No. 2004-054190 US Patent Application Publication No. 2016/228587

Kozikowski AP, et al., J. Med. Chem. 47: 1729-38 (2004)

の化合物、またはその薬学的に許容される塩であって、
式中、
Ｚはキレート化部分、またはＺ^１：

の構造を有する基であり、
ここで、Ｙ^１０はＣＨまたはＮであり；
ＬおよびＬ^ａのそれぞれは独立して、結合、または１から６個の炭素原子を鎖、環、またはこれらの組合せ中に含む２価の連結部分であり、少なくとも１個の炭素原子は必要に応じてＯ、－ＮＲ^３－、または－Ｃ（Ｏ）－で置き換えられ；
Ｒ^＊は、放射性同位体であり；
Ｒ^２２は、アルキル、アルコキシル、ハロゲン化物、ハロアルキル、およびＣＮからなる群から選択され；
ｐは、０から４の整数であり、ｐが１より大きい場合、各Ｒ^２２は同じまたは異なり；
Ｗは、ＰＳＭＡ標的リガンドであり；
各Ｔ^１は独立して、Ｔ^１１またはＴ^１２：

の構造を有し、
ここで、Ｒ^２３は－（ＣＨ_２）_ａＣＯ_２Ｈであり、ａは０から４の整数であり；
各Ｔ^２は独立して、Ｔ^２１またはＴ^２２：

の構造を有し、
ここで、ｂは、１から６の整数であり、Ｇ^１は、Ｏ、Ｓ、またはＮＲ^３であり；
ｑは、０、１、２、または３であり；
ｒは、０、１、または２であり；
Ａ^２は、結合、または１から２０個の炭素原子を鎖、環、またはこれらの組合せ中に含む２価の連結部分であり、１個またはそれより多くの炭素原子は必要に応じてＯ、－ＮＲ^４０－、または－Ｃ（Ｏ）－で置き換えられ得；
Ｂ^２は、Ｈ、

であり、
ここで、ｃは、１から４の整数であり、
Ｇは、Ｏ、Ｓ、またはＮＲ^３であり；
Ｘ^２は、Ｏ、Ｓ、または－ＮＲ^４１－であり；
Ｒ^３、Ｒ^４０、およびＲ^４１のそれぞれは独立して、水素、アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、アルキルアリール、およびヘテロアリールからなる群から選択され、
Ｒ^３１、Ｒ^３２、Ｒ^３３、Ｒ^３４、Ｒ^３５、およびＲ^３６のそれぞれは独立して、水素、アルキル、アルコキシル、またはハロゲン化物であり；
Ｒ^３７およびＲ^３８のそれぞれは独立して、水素、アルキル、アリール、またはアルキルアリールであり；
各Ｒ^３９は独立して、アルキル、アルコキシル、ハロゲン化物、ハロアルキル、およびＣＮからなる群から選択され；
ｓは、０または１であり；
ｖは、０から４の整数であり、ｖが１より大きい場合、各Ｒ^３９は同じまたは異なり；
ただしｓが１であり、－Ｘ^２－Ａ^２－Ｂ^２が－ＯＨであり、ｒが０であり、ｑが１であり、Ｔ^１がＴ^１１である場合、Ｚが、Ｚ^１または

であることはない、化合物、またはその薬学的に許容される塩に関する。 Outline of the Invention In one embodiment, the present disclosure is based on Formula I :.

Compound, or a pharmaceutically acceptable salt thereof,
During the ceremony
Z is the chelated moiety, or Z ¹ :

It is a group having the structure of
Where Y ¹⁰ is CH or N;
Each of L and La is independently ^a bond, or a divalent link containing 1 to 6 carbon atoms in a chain, ring, or combination thereof, requiring at least one carbon atom. Replaced by O, -NR ^3- , or -C (O)-accordingly;
R ^* is a radioisotope;
R ²² is selected from the group consisting of alkyl, alkoxyl, halides, haloalkyl, and CN;
p is an integer from 0 to 4, and if p is greater than 1, each R ²² is the same or different;
W is a PSMA target ligand;
Each T ¹ is independently T ¹¹ or T ¹² :

Has the structure of
Here, R ²³ is − (CH ₂ ) _a CO ₂ H, and a is an integer from 0 to 4;
Each T ² is independently T ²¹ or T ²² :

Has the structure of
Where b is an integer from 1 to 6 and G ¹ is O, S, or NR ³ ;
q is 0, 1, 2, or 3;
r is 0, 1, or 2;
A ² is a bond, or a divalent linking moiety containing 1 to 20 carbon atoms in a chain, ring, or combination thereof, with one or more carbon atoms O, as needed. Can be replaced with -NR ⁴⁰ -or-C (O)-;
B ² is H,

And
Where c is an integer from 1 to 4 and
G is O, S, or NR ³ ;
X ² is O, S, or -NR ^41- ;
Each of R ³ , R ⁴⁰ , and R ⁴¹ is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl.
R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , and R ³⁶ are each independently hydrogen, alkyl, alkoxyl, or halide;
Each of R ³⁷ and R ³⁸ is independently hydrogen, alkyl, aryl, or alkylaryl;
Each R ³⁹ is independently selected from the group consisting of alkyl, alkoxyl, halides, haloalkyl, and CN;
s is 0 or 1;
v is an integer from 0 to 4, and if v is greater than 1, each R ³⁹ is the same or different;
Where s is 1, -X ² -A ² -B ² is -OH, r is 0, q is 1, and T ¹ is T ¹¹ , then Z is Z ¹ or

With respect to a compound, or a pharmaceutically acceptable salt thereof, which is not.

In one embodiment, the disclosure relates to a method of imaging a subject, comprising administering to the subject the radiolabeled compound disclosed herein; and obtaining an image of the subject or a portion of the subject. In another embodiment, the method for imaging comprises obtaining an image on a device capable of detecting positron emission.

Further, the present disclosure relates to a method of making a compound of formula I.

In another embodiment, the disclosure relates to a method for treating one or more tumors of a subject, comprising administering to the subject an effective amount of a compound or complex disclosed herein. In some embodiments, the tumor is a PSMA overexpressing tumor. In some embodiments, the tumor is a prostate tumor, a neuroendocrine tumor, or an endocrine tumor. In some embodiments, the tumor is a prostate tumor.

FIG. 1 shows an HPLC chromatogram of the radiolabel [ ⁶⁸ Ga] 4. Stationary phase: Eclipse XDB-C18 column 5μ; 4.6 × 150mm; Mobile phase: A: 0.1% TFA / water; B: 0.1% TFA / ACN; Gradient: 0-8 minutes A / B 100 / 0-0 / 100; 2 mL / min.

FIG. 2 shows an HPLC chromatogram of the radiolabel [ ¹⁷⁷ Lu] 4. Stationary phase: Eclipse XDB-C18 column 5μ; 4.6 × 150mm; Mobile phase: A: 0.1% TFA / water; B: 0.1% TFA / ACN; Gradient: 0-4 minutes A / B 85 / 15-0 / 100, 4-11 minutes A / B 85/15 to 30/70, 11-14 minutes A / B 30/70 to 85/15; 1 mL / min.

FIG. 3 shows an HPLC chromatogram of a radiotrace of a radiolabeled protective intermediate [ ¹²⁵ I] 24, a cold standard 26, and a final compound [ ¹²⁵ I] 26. Fixed phase: Agilent Chromatography 120 EC-C18 column 2.7μ, 4.6 × 50mm; Mobile phase: A: 0.1% TFA / water; B: 0.1% TFA / ACN; Gradient: 0 to 1 minute A / B 80/20, 1 to 16 minutes A / B 80/20 to 0/100, 16 to 16.5 minutes A / B 0/100 to 80/20, 16.5 to 20 minutes A / B 80/20 2 mL / min.

Detailed Description of the Invention Many different radionuclides and many different precision targets have been reported [8]. The Theranostic approach provides a personalized approach for precision medicine. One of the suitable isotopes is Lu-177 [8, 18, 19]. Lutetium-177 (Lu-177), which has a physical half-life of 6.65 days, is a suitable therapeutic radionuclide, beta-ray (490 keV), gamma-ray, and X-ray (113 keV (3%), 210 keV (113 keV (3%), 210 keV). 11%)) is released.

Radiolabels have been prepared for diagnostic imaging and radionuclide therapy, based on agents that target PSMA overexpressing in most prostate cancer patients. ¹⁷⁷ Lu-labeled PSMA-617 and DOTAG A- (yl) -fk (sub-KuE) (PSMA-I & T) have been reported as PSMA-targeted radionuclide therapies (see Discussions [10-13] [14] [15]. The results of clinical trials on PSMA-617 [16] and PSMA-I & T [17] as radionuclide therapies were very promising.

Over the last two decades, there have been numerous reports of the use of radiometal-labeled small molecules and peptides to image various tumors. Among them, [ ⁶⁸ Ga] DOTA-TOC, [ ⁶⁸ Ga] DOTA-TATE, and [ ⁶⁸ Ga] DOTA-NOC are commonly used for the detection of neuroendocrine tumors (NETs) expressing somatostatin receptors. It is a drug. Recently, [ ⁶⁸ Ga] PSMA-11 has been reported to be an effective PET contrast agent targeting the overexpression of PSMA in prostate cancer patients.

Additional chelates for making lutetium (Lu-177) -labeled radionuclide therapeutics have been reported. Chelating groups include many cyclic and acyclic polyazacarboxylic acids (Scheme 6), each having a stability constant (logK _d ) between 15 and 30. These improved chelates, 1,4,7,10-tetraazacyclodocecane, 1- (glutaric acid) -4,7,10-triacetic acid (DOTAGA) , And 1,4,7,10-tetraazacyclodosecan, 1,7- (diglutaric acid) -4,10-diacetic acid (DOTA (GA) 2) form a stable ¹⁷⁷ Lu-labeled complex at room temperature. (Ie stable in vitro and in vivo), which simplifies preparation and is more suitable for clinical situations.

Many of the compounds of the present disclosure include DOTAGA and DOTA (GA) 2, both of which are various radioactive metals including ⁶⁸ Ga (for diagnostics) [6] and ¹⁷⁷ Lu (for radionuclide therapy) [7]. A stable chelated complex having (M) can be formed (Scheme 6).

In the compounds or complexes disclosed herein, in vivo biodistribution properties are improved by specific modification of the chemical structure of these compounds, such as iodination and lutetium-labeled PSMA inhibitors (eg, linker changes). Will be done. Structural regulation resulted in higher tumor uptake and faster renal excretion (reduced non-target radiation dose) in PSMA tumor-carrying mice.

These new agents are valuable in radionuclide therapy when labeled with beta or alpha-releasing isotopes; however, these agents are also useful as diagnostic agents when labeled with gamma-releasing isotopes. be.

Compounds with novel phenoxylinkers have been reported. See US Patent Application Publication No. 2017/0189568, which is incorporated herein by reference in its entirety. This series of PSMA inhibitors, including the substructure of the urea-based PSMA target moiety and novel linkers for various chelating groups, resulted in stable metal complexes, including Lu-177. These were tested by in vitro binding, tumor cell uptake, and in vivo biodistribution studies. These PSMA inhibitors showed good binding affinity and in vivo targeting ability of prostate tumor-carrying nude mice. For example, novel PSMA inhibitors can have chelated moieties such as complex or compound A; or they are a: radioactive metal DOTAGA complex, b: radioactive metal DOTA (GA) 2 complex, or c: radioactive. It can have a halogen (Scheme 7).

の化合物、またはその薬学的に許容される塩であって、
式中、
Ｚはキレート化部分、またはＺ^１：

の構造を有する基であり、
ここで、Ｙ^１０はＣＨまたはＮであり；
ＬおよびＬ^ａのそれぞれは独立して、結合、または１から６個の炭素原子を鎖、環、またはこれらの組合せ中に含む２価の連結部分であり、少なくとも１個の炭素原子は必要に応じてＯ、－ＮＲ^３－、または－Ｃ（Ｏ）－で置き換えられ；
Ｒ^＊は、放射性同位体であり；
Ｒ^２２は、アルキル、アルコキシル、ハロゲン化物、ハロアルキル、およびＣＮからなる群から選択され；
ｐは、０から４の整数であり、ｐが１より大きい場合、各Ｒ^２２は同じまたは異なり；
Ｗは、ＰＳＭＡ標的リガンドであり；
各Ｔ^１は独立して、Ｔ^１１またはＴ^１２：

の構造を有し、
ここで、Ｒ^２３は－（ＣＨ_２）_ａＣＯ_２Ｈであり、ａは０から４の整数であり；
各Ｔ^２は独立して、Ｔ^２１またはＴ^２２：

の構造を有し、
ここで、ｂは、１から６の整数であり、Ｇ^１は、Ｏ、Ｓ、またはＮＲ^３であり；
ｑは、０、１、２、または３であり；
ｒは、０、１、または２であり；
Ａ^２は、結合、または１から２０個の炭素原子を鎖、環、またはこれらの組合せ中に含む２価の連結部分であり、１個またはそれより多くの炭素原子は必要に応じてＯ、－ＮＲ^４０－、または－Ｃ（Ｏ）－で置き換えられ得；
Ｂ^２は、Ｈ、

であり、
ここで、ｃは、１から４の整数であり、
Ｇは、Ｏ、Ｓ、またはＮＲ^３であり；
Ｘ^２は、Ｏ、Ｓ、または－ＮＲ^４１－であり；
Ｒ^３、Ｒ^４０、およびＲ^４１のそれぞれは独立して、水素、アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、アルキルアリール、およびヘテロアリールからなる群から選択され、
Ｒ^３１、Ｒ^３２、Ｒ^３３、Ｒ^３４、Ｒ^３５、およびＲ^３６のそれぞれは独立して、水素、アルキル、アルコキシル、またはハロゲン化物であり；
Ｒ^３７およびＲ^３８のそれぞれは独立して、水素、アルキル、アリール、またはアルキルアリールであり；
各Ｒ^３９は独立して、アルキル、アルコキシル、ハロゲン化物、ハロアルキル、およびＣＮからなる群から選択され；
ｓは、０または１であり；
ｖは、０から４の整数であり、ｖが１より大きい場合、各Ｒ^３９は同じまたは異なり；
ただしｓが１であり、－Ｘ^２－Ａ^２－Ｂ^２が－ＯＨであり、ｒが０であり、ｑが１であり、Ｔ^１がＴ^１１である場合、Ｚが、Ｚ^１または

であることはない、化合物、またはその薬学的に許容される塩に関する。 In one embodiment, the present disclosure comprises formula I:

Compound, or a pharmaceutically acceptable salt thereof,
During the ceremony
Z is the chelated moiety, or Z ¹ :

It is a group having the structure of
Where Y ¹⁰ is CH or N;
Each of L and La is independently ^a bond, or a divalent link containing 1 to 6 carbon atoms in a chain, ring, or combination thereof, requiring at least one carbon atom. Replaced by O, -NR ^3- , or -C (O)-accordingly;
R ^* is a radioisotope;
R ²² is selected from the group consisting of alkyl, alkoxyl, halides, haloalkyl, and CN;
p is an integer from 0 to 4, and if p is greater than 1, each R ²² is the same or different;
W is a PSMA target ligand;
Each T ¹ is independently T ¹¹ or T ¹² :

Has the structure of
Here, R ²³ is − (CH ₂ ) _a CO ₂ H, and a is an integer from 0 to 4;
Each T ² is independently T ²¹ or T ²² :

Has the structure of
Where b is an integer from 1 to 6 and G ¹ is O, S, or NR ³ ;
q is 0, 1, 2, or 3;
r is 0, 1, or 2;
A ² is a bond, or a divalent linking moiety containing 1 to 20 carbon atoms in a chain, ring, or combination thereof, with one or more carbon atoms O, as needed. Can be replaced with -NR ⁴⁰ -or-C (O)-;
B ² is H,

And
Where c is an integer from 1 to 4 and
G is O, S, or NR ³ ;
X ² is O, S, or -NR ^41- ;
Each of R ³ , R ⁴⁰ , and R ⁴¹ is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl.
R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , and R ³⁶ are each independently hydrogen, alkyl, alkoxyl, or halide;
Each of R ³⁷ and R ³⁸ is independently hydrogen, alkyl, aryl, or alkylaryl;
Each R ³⁹ is independently selected from the group consisting of alkyl, alkoxyl, halides, haloalkyl, and CN;
s is 0 or 1;
v is an integer from 0 to 4, and if v is greater than 1, each R ³⁹ is the same or different;
Where s is 1, -X ² -A ² -B ² is -OH, r is 0, q is 1, and T ¹ is T ¹¹ , then Z is Z ¹ or

With respect to a compound, or a pharmaceutically acceptable salt thereof, which is not.

In some embodiments, Z is the chelated moiety. The chelated moiety is known in the art and refers to a metal binding group. In some embodiments, Z comprises the group consisting of DOTA, NOTA, NODAGA, DOTAGA, DOTA (GA) 2, TRAP, NOPO, PCTA, DFO, DTPA, CHX-DTPA, AAZTA, DEDPA, and oxo-DO3A. The chelated moiety of choice. These chelated moieties are 1,4,7,10-tetraazacyclododecane-N, N', N'', N'''-tetraacetic acid (DOTA), 1,4,7-triazacyclononane. -1,4,7-Triacetic acid (NOTA), 2- (4,7-bis (carboxymethyl) -1,4,7-triazonan-1-yl) pentandioic acid (NODAGA), 1,4,7 , 10-Tetraazacyclodosecan, 1- (glutaric acid) -4,7,10-triacetic acid (DOTAGA), and 1,4,7,10-tetraazacyclodosecan, 1,7- (diglutaric acid) ) -4,10-Diacetic acid (DOTA (GA) 2), 1,4,7-triazacyclononanphosphinic acid (TRAP), 1,4,7-triazacyclononan-1- [methyl (2-) Carboxyethyl) phosphinic acid] -4,7-bis [methyl (2-hydroxymethyl) phosphinic acid] (NOPO), 3,6,9,15-tetraazabicyclo [9.3.1. ] Pentadeca-1 (15), 11,13-Triene-3,6,9-Triacetic acid (PCTA), N'-{5- [acetyl (hydroxy) amino] pentetic} -N- [5-({4) -[(5-Aminopentyl) (hydroxy) amino] -4-oxobutanoyl} amino) pentetic] -N-hydroxysuccinamide (DFO), diethylenetriaminepentetic acid (DTPA), Trans-cyclohexyl-diethylenetriaminepentaacetic acid ( CHX-DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1- (p-isothiocyanatobenzyl) -3-methyl-DTPA (1B3M), 2- (p-isothiocyanatobenzyl) -4-methyl-DTPA (1M3B), 1- (2) -methyl-4- It is derived from isocyanatobenzyl-DTPA (MX-DTPA). Useful chelated moieties are disclosed in US 2016/0228587, which is incorporated herein by reference in its entirety.

であり、
Ａ^１は、結合、または１から２０個の炭素原子を鎖、環、またはこれらの組合せ中に含む２価の連結部分であり、１個またはそれより多くの炭素原子は必要に応じてＯ、－ＮＲ^４０－、または－Ｃ（Ｏ）－で置き換えられ得；
Ｂ^１は、Ｈ、

であり、
ここで、ｃは、１から４の整数であり；
Ｘ^１は、Ｏ、Ｓ、または－ＮＲ^４１－であり；
Ｄは、１，４，７，１０－テトラアザシクロドデカン－１，４，７，１０－四酢酸から誘導される２価のキレート化基である。 In some embodiments, Z is

And
A ¹ is a bond, or a divalent linking moiety containing 1 to 20 carbon atoms in a chain, ring, or combination thereof, with one or more carbon atoms optionally O, Can be replaced with -NR ⁴⁰ -or-C (O)-;
B ¹ is H,

And
Where c is an integer from 1 to 4;
X ¹ is O, S, or -NR ^41- ;
D is a divalent chelating group derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

からなる群から選択される。これらの２価のキレート化基では、右上の結合部位がＴ^１基に接続され、底部結合部位はＸ^１基に接続される。 In some embodiments, D is

It is selected from the group consisting of. In these divalent chelating groups, the ^upper right binding site is connected to the T1 group and the ^bottom binding site is connected to the X1 group.

からなる群から選択される。 In some embodiments, D is

It is selected from the group consisting of.

からなる群から選択される。 In some embodiments, D is

It is selected from the group consisting of.

In some embodiments, A ¹ is a bond, or divalent linking moiety, a divalent linking moiety comprising 1 to 16 carbon atoms in a chain, ring, or combination thereof. One or more carbon atoms can be replaced with O, -NR ^40- , or -C (O)-as needed. In some embodiments, A ¹ binds, or-(CH ₂ ) _n -,-(CH ₂ ) _n C (O) NH-,-(CH ₂ CH ₂ O) _n- , or-(CH 2) n-, ₂ CH ₂ O) _n (CH ₂ CH ₂ NH) _n- ;
Each n is independently 1, 2, 3, or 4. In some embodiments, A ¹ is binding,-(CH ₂ ) _n C (O) NH-, or-(CH ₂ CH ₂ O) _n (CH ₂ CH ₂ NH) _n- ; n is. 1, 2, or 3. In some embodiments, A ¹ is a binding,-(CH ₂ ) C (O) NH- or-(CH ₂ CH ₂ O) ₂ (CH ₂ CH ₂ NH)-.

であり、ここで、ｃは１から３の整数である。一部の実施形態では、ｃが３である。 In some embodiments, B ² is H,

Where c is an integer from 1 to 3. In some embodiments, c is 3.

である。 In some embodiments, X ¹ is O or -NH-. In some embodiments, X ¹ is O, A ¹ is a bond, and B ¹ is H. In some embodiments, X ¹ is -NH- and A ¹ is-(CH ₂ ) C (O) NH- or-(CH ₂ CH ₂ O) ₂ (CH ₂ CH ₂ NH)-. Yes, B ¹ is

Is.

からなる群から選択される。 In some embodiments, Z is

It is selected from the group consisting of.

からなる群から選択される。 In some embodiments, Z is

It is selected from the group consisting of.

の構造を有する基であり、
ここで、Ｙ^１０はＣＨまたはＮであり；
ＬおよびＬ^ａのそれぞれは独立して、結合、または１から６個の炭素原子を鎖、環、またはこれらの組合せ中に含む２価の連結部分であり、少なくとも１個の炭素原子は、必要に応じてＯ、－ＮＲ^３－、または－Ｃ（Ｏ）－で置き換えられ；
Ｒ^＊は、放射性同位体であり；
Ｒ^２２は、アルキル、アルコキシル、ハロゲン化物、ハロアルキル、およびＣＮからなる群から選択され；
ｐは、０から４の整数であり、ｐが１より大きい場合、各Ｒ^２２は同じまたは異なる。 In some embodiments, Z is Z ¹ :

It is a group having the structure of
Where Y ¹⁰ is CH or N;
Each of L and La is independently ^a bond, or a divalent link containing 1 to 6 carbon atoms in a chain, ring, or combination thereof, and at least one carbon atom is required. Replaced by O, -NR ^3- , or -C (O)-depending on;
R ^* is a radioisotope;
R ²² is selected from the group consisting of alkyl, alkoxyl, halides, haloalkyl, and CN;
p is an integer from 0 to 4, and if p is greater than 1, each R ²² is the same or different.

Useful radioisotopes (ie, radioisotopes) include positron emitting and photon emitting isotopes. Radioisotopes are known in the art and they can be, for example, ¹¹ C, ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, and ²¹¹ As. ¹²⁴ I can be used for PET imaging. ²¹¹ As can be used for radionuclide therapy. In some embodiments, the radioisotope is a radioactive halogen. In some embodiments, the radioisotope emits photons and can be used in SPECT, such as ¹²³ I and ¹³¹ I.

In some embodiments, L is a bond, or a divalent link containing 1 to 6 carbon atoms in a chain, ring, or combination thereof, and at least one carbon atom is required. It is replaced by O, -NR ^3- , or -C (O)-, depending on the situation. In some embodiments, L is a bond. In another embodiment, L is a divalent link comprising a C ₁ to C ₆ alkylene group, where at least one carbon atom is optionally O, -NR ^3- , or -C. It is replaced by (O)-. In some embodiments, L is (CH ₂ ) _n ,-(OCH ₂ CH ₂ ) _n -,-(NHCH ₂ CH ₂ ) _n- , or -C (O) (CH ₂ ) _n- . Here, n is 1, 2, or 3. In another embodiment, L is —OCH ₂ CH _2- . Other useful examples of divalent linked moieties include -CH _2- , -CH ₂ CH _2- , -CH ₂ CH ₂ CH _2- , -OCH ₂ CH ₂ CH _2- , -NHCH ₂ CH _2- , -NHCH ₂ CH ₂ CH _2- , -COCH _{2-, -COCH 2 CH 2-, and -COCH 2 CH 2 CH 2- are} included.

In some embodiments, La is ^a bond, or a divalent link containing 1 to 6 carbon atoms in a chain, ring, or combination thereof, and at least one carbon atom is required. It is replaced with O, -NR ^3- , or -C (O)-depending on. In another embodiment, La is ^a divalent linking moiety containing C ₁ to C ₆ alkylene groups, and at least one carbon atom is O, -NR ^3- , or -C (as needed). O)-replaced by-. In some embodiments, ^La is —C (O) —.

In some embodiments, R ²² is selected from the group consisting of C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxyl, halides, halo C ₁ to C ₄ alkyl, and CN. In some embodiments, p is 0, 1, or 2. In some embodiments, p is zero.

In some embodiments, Y ¹⁰ is CH. In some embodiments, Y ¹⁰ is N.

を有し、
ここで、Ｉ（ヨウ素）は放射性である。一部の実施形態では、放射性ヨウ素が^１２５Ｉである。一部の実施形態では、放射性ヨウ素が^１３１Ｉである。 In some embodiments, Z is the structure:

Have,
Here, I (iodine) is radioactive. In some embodiments, the radioactive iodine is ¹²⁵ I. In some embodiments, the radioactive iodine is ¹³¹ I.

PSMA targeting ligands are known in the art and they refer to groups capable of binding to PSMA. The PSMA targeting ligand can be a urea-based ligand system discussed herein.

を有し、
ここで、Ｒ^２０およびＲ^２１はそれぞれ独立して、アミノ酸残基であって、そのアミノ基を介して隣接する－Ｃ（Ｏ）－基に連結されているアミノ酸残基である。 In some embodiments, the PSMA target ligand W is structured:

Have,
Here, R ²⁰ and R ²¹ are independent amino acid residues, which are amino acid residues linked to the adjacent —C (O) -group via the amino group thereof.

を有し、
ここで、Ｒ^２は、水素またはカルボン酸保護基であり、ｘは１から６の整数であり、ｙは１から４の整数である。一実施形態では、Ｗは、構造：

を有する。 In some embodiments, W is a structure:

Have,
Here, R ² is a hydrogen or carboxylic acid protecting group, x is an integer of 1 to 6, and y is an integer of 1 to 4. In one embodiment, W is the structure:

Have.

In certain embodiments, the compounds of the present disclosure are represented by Generalized Formula I and accompanying definitions.

を有し、
ここで、Ｒ^２３は、－（ＣＨ_２）_ａＣＯ_２Ｈであり、ａは０から４の整数である。一部の実施形態では、ａが０、１、または２である。一部の実施形態では、ａが２である。 Part- [T ¹ ] _q- [T ² ] _r -represents a connecting part. In some embodiments, each T ¹ is independent and has a structure of T ¹¹ or T ¹² .

Have,
Here, R ²³ is − (CH ₂ ) _a CO ₂ H, and a is an integer from 0 to 4. In some embodiments, a is 0, 1, or 2. In some embodiments, a is 2.

である。 In some embodiments, the T ¹² is

Is.

である。 In some embodiments,-[T ¹ ] _q -is

Is.

の構造を有し、
ここで、ｂは１から６の整数であり、Ｇ^１は、Ｏ、Ｓ、またはＮＲ^３である。一部の実施形態では、ｂが１、２、３、または４である。一部の実施形態では、ｂが３または４である。一部の実施形態では、Ｇ^１がＯまたは－ＮＨ－である。一部の実施形態では、Ｇ^１がＯである。一部の実施形態では、Ｒ^３１およびＲ^３２のそれぞれが独立して、水素、Ｃ_１～Ｃ_４アルキル、Ｃ_１～Ｃ_４アルコキシル、またはハロゲン化物である。一部の実施形態では、Ｒ^３１およびＲ^３２の両方が水素である。 In some embodiments, each T ² is independently T ²¹ or T ²² :.

Has the structure of
Where b is an integer from 1 to 6 and G ¹ is O, S, or NR ³ . In some embodiments, b is 1, 2, 3, or 4. In some embodiments, b is 3 or 4. In some embodiments, G ¹ is O or -NH-. In some embodiments, G ¹ is O. In some embodiments, R ³¹ and R ³² are each independently hydrogen, C1 _{- C4} alkyl, C1 _{- C4} alkoxyl, or halide. In some embodiments, both R ³¹ and R ³² are hydrogen.

である。 In some embodiments,-[T ² ] _r -is

Is.

In some embodiments, A ² is a bond, or a divalent linking moiety containing 1 to 16 carbon atoms in a chain, ring, or combination thereof, with one or more carbon atoms. , Can be replaced with O, -NR ^40- , or -C (O)-if desired. In some embodiments, A ² binds, or-(CH ₂ ) _n -,-(CH ₂ ) _n C (O) O-,-(CH ₂ ) _n C (O) NH-,-( CH ₂ CH ₂ O) _n -or-(CH ₂ CH ₂ O) _n (CH ₂ CH ₂ NH) _n- ; each n is independently 1, 2, 3, or 4. In some embodiments, A ² is bound or-(CH ₂ ) _n C (O) NH-; n is 1, 2, or 3. In some embodiments, A ² is bound or-(CH ₂ ) C (O) NH-.

であり、ここで、ｃは１から３の整数である。一部の実施形態では、ｃが３である。 In some embodiments, B ² is H,

Where c is an integer from 1 to 3. In some embodiments, c is 3.

である。 In some embodiments, X ² is O or -NH-. In some embodiments, X ² is O, A ² is a bond, and B ² is H. In some embodiments, X ² is -NH-, A ² is bound or-(CH ₂ ) C (O) NH-, and B ² is.

Is.

In some embodiments, R ³ , R ⁴⁰ , and R ⁴¹ are independent of hydrogen, C ₁ to C ₄ alkyl, C ₁ to C ₆ cycloalkyl, heterocycloalkyl, aryl, C ₁ to C, respectively. It is selected from the group consisting of ₄ alkylaryls and heteroaryls. In some embodiments, each of R ³ , R ⁴⁰ , and R ⁴¹ is hydrogen.

In some embodiments, each of R ³³ , R ³⁴ , R ³⁵ , and R ³⁶ is independently hydrogen, C1 _{- C4} alkyl, C1 _{- C4} alkoxyl, or halide. In some embodiments, R ³³ , R ³⁴ , R ³⁵ , and R ³⁶ are hydrogen.

In some embodiments, R ³⁷ and R ³⁸ are each independently hydrogen, C1 _{- C4} alkyl, aryl, or C1 _{- C4} alkylaryl. In some embodiments, each of R ³⁷ and R ³⁸ is independently hydrogen, phenyl, benzyl, or methylnaphthyl.

In some embodiments, each R ³⁹ is independently selected from the group consisting of C ₁ to C ₄ alkyl, C ₁ to C ₄ alkoxyl, halide, halo C ₁ to C ₄ alkyl, and CN. In some embodiments, each R ³⁹ is independently methyl, methoxyl, halomethyl, or a halide. In some embodiments, v is 0, 1, or 2. In some embodiments, v is zero.

の構造、またはその薬学的に許容される塩を有し、式中、Ｒ^３７ａは必要に応じて置換されたフェニルまたは必要に応じて置換されたナフチルである。 In some embodiments, the compound of formula I is formulated I-A :.

In the formula, R ^37a is optionally substituted phenyl or optionally substituted naphthyl.

の構造、またはその薬学的に許容される塩を有し、式中、Ｒ^３７ａは、必要に応じて置換されたフェニルまたは必要に応じて置換されたナフチルである。 In some embodiments, the compound of formula I is formulated IB :.

In the formula, R ^37a is optionally substituted phenyl or optionally substituted naphthyl.

の構造、またはその薬学的に許容される塩を有し、式中、ｑは１または２である。 In some embodiments, the compound of formula I has the formula:

Has a structure of, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2 in the formula.

の構造、またはその薬学的に許容される塩を有し、式中、ｑは１または２である。 In some embodiments, the compound of formula I has the formula:

Has a structure of, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2 in the formula.

の構造、またはその薬学的に許容される塩を有する。 In some embodiments, the compound of formula I is formulated III-A :.

Has a structure of, or a pharmaceutically acceptable salt thereof.

の構造、またはその薬学的に許容される塩を有する。 In some embodiments, the compound of formula I is formulated III-B:

Has a structure of, or a pharmaceutically acceptable salt thereof.

の構造、またはその薬学的に許容される塩を有する。 In some embodiments, the compound of formula I is formulated IV-A or IV-B :.

Has a structure of, or a pharmaceutically acceptable salt thereof.

In some embodiments, R ^37a is aryl. In one embodiment, R ^37a is optionally substituted phenyl. In another embodiment, R ^37a is a optionally substituted naphthyl. In some embodiments, R ^37a is phenyl.

The definitions of A ¹ , B ¹ , X ¹ , A ² , B ² , X ² , T ¹ , T ² , q, r, Z, and W described above with respect to Formula I are those defined in Formulas IA, IB, Any of II-A, II-B, II-C, II-D, II-AA, II-BB, II-CC, II-DD, III-A, III-B, IV-A, and IV-B Applies to.

またはその薬学的に許容される塩を有する。 In some embodiments, the compound of formula I has the following structure:

Or have its pharmaceutically acceptable salt.

またはその薬学的に許容される塩を有し、ここで、Ｉ（ヨウ素）は放射性である。一部の実施形態では、放射性ヨウ素が^１２５Ｉである。一部の実施形態では、放射性ヨウ素が^１３１Ｉである。 In some embodiments, the compound of formula I has the following structure:

Or it has a pharmaceutically acceptable salt thereof, where I (iodine) is radioactive. In some embodiments, the radioactive iodine is ¹²⁵ I. In some embodiments, the radioactive iodine is ¹³¹ I.

In some embodiments, the present disclosure relates to a complex comprising a compound of formula I disclosed herein chelated to metal M, where Z is a chelated moiety. In some embodiments, the metal M is ²²⁵ Ac, ⁴⁴ Sc, ⁴⁷ Sc, ^203/212 Pb, ⁶⁷ Ga, ⁶⁸ Ga, ⁷² As, ^{99 m} Tc, ¹¹¹ In, ⁹⁰ Y, ⁹⁷ Ru, ⁶² Cu, ⁶⁴ . Cu, ⁵² Fe, ^52m Mn, ¹⁴⁰ La, ¹⁷⁵ Yb, ¹⁵³ Sm, ¹⁶⁶ Ho, ¹⁴⁹ Pm, ¹⁷⁷ Lu, ¹⁴² Pr, ¹⁵⁹ Gd, ²¹³ Bi, ⁶⁷ Cu, ¹¹¹ Ag, ¹⁹⁹ Au, ^{161 Cr} It is selected from the group consisting of. In some embodiments, the metal M is ⁶⁸ Ga or ¹⁷⁷ Lu. In some embodiments, the metal M is ⁶⁸ Ga. In some embodiments, the metal M is ¹⁷⁷ Lu.

An attractive and versatile method for obtaining radiopharmaceuticals for PET / CT is the use of ⁶⁸ Ge / ⁶⁸ Ga generators to produce ⁶⁸ Ga (T _1/2 = 68 minutes) PET contrast agents. .. There are several advantages to using ⁶⁸ Ga for PET imaging: (1) a short-lived positron emitter (half-life 68 minutes, β ⁺ ). (2) The ⁶⁸ Ge / ⁶⁸ Ga generator easily produces ⁶⁸ Ga in a laboratory device without a cyclotron nearby. (3) The parental ⁶⁸ Ge has a physical half-life of 270 days, resulting in an effective lifespan of 6 to 12 months. (4) There are several commercial vendors currently supplying this generator for clinical practice on a daily basis. (5) Coordination chemistry for Ga (III) is very flexible, and numerous Ga chelates with various stability constants and metal chelation selectivity have been reported; ⁶⁸ Ga radiopharmaceuticals are used for cancer diagnosis. It has been demonstrated to target a variety of tissue or physiological processes.

またはその薬学的に許容される塩を有し、ここで、Ｘ^１、Ｘ^２、Ａ^１、Ａ^２、Ｂ^１、Ｂ^２、およびＭは、本明細書で定義される。一部の実施形態では、Ｘ^１がＯまたは－ＮＨ－であり；Ｘ^２がＯまたは－ＮＨ－であり；Ａ^１は、結合、－（ＣＨ_２）Ｃ（Ｏ）ＮＨ－、または－（ＣＨ_２ＣＨ_２Ｏ）_２（ＣＨ_２ＣＨ_２ＮＨ）－であり；Ａ^２は、結合、または－（ＣＨ_２）Ｃ（Ｏ）ＮＨ－であり；Ｂ^１およびＢ^２のそれぞれは、独立して、Ｈ、

である。 In some embodiments, the complex has a structure:

Or having a pharmaceutically acceptable salt thereof, wherein X ¹ , X ² , A ¹ , A ² , B ¹ , B ² , and M are defined herein. In some embodiments, X ¹ is O or -NH-; X ² is O or -NH-; A ¹ is binding,-(CH ₂ ) C (O) NH-, or-( CH ₂ CH ₂ O) ₂ (CH ₂ CH ₂ NH)-; A ² is bound, or-(CH ₂ ) C (O) NH-; B ¹ and B ² are independent of each other. H,

Is.

またはその薬学的に許容される塩を有する。 In some embodiments, the complex has a structure:

Or have its pharmaceutically acceptable salt.

In one embodiment, the present disclosure relates to a method of making a compound of formula I or a complex thereof.

In one embodiment, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or complex disclosed herein. The disclosure also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically acceptable salt of a compound or complex disclosed herein.

In one embodiment, the present disclosure is a compound of formula I or a pharmaceutically acceptable i. v. A kit formulation comprising a sterile container containing an isotonic solution for injection and instructions for use in diagnostic imaging (eg, ⁶⁸ Ga) and radiation therapy (eg, ¹¹⁷ Lu) is provided.

The present disclosure is for in vivo imaging comprising administering to a subject an effective amount of a radioactive metal complex or radioactive compound disclosed herein and detecting the pattern of radioactivity of the complex or compound in the subject. Also provides the method of. In one embodiment, the disclosure relates to a method for imaging a subject, comprising administering to the subject the radiolabeled compound disclosed herein; and obtaining an image of the subject or a portion of the subject. .. In another embodiment, the method for imaging comprises obtaining an image on a device capable of detecting positron emission.

The present disclosure comprises administering to a subject an effective amount of a radioactive metal complex or radioactive compound disclosed herein and detecting the pattern of radioactivity of the complex or compound in said subject in vivo imaging. It also provides a method.

The present disclosure provides a method of treating one or more tumors in a subject, comprising administering to the subject an effective amount of a radioactive metal complex or radioactive compound disclosed herein. In some embodiments, the tumor is a PSMA overexpressing tumor. In some embodiments, the tumor is a prostate tumor, a neuroendocrine tumor, or an endocrine tumor. In some embodiments, the tumor is a prostate tumor.

Typical subjects to whom the compounds of the present disclosure can be administered are mammals, especially primates, especially humans. For veterinary applications, various subjects, such as livestock such as cows, sheep, goats, cows, pigs; poultry such as chickens, ducks, geese, citrus, etc .; pet animals, especially dogs and cats. Such pets are appropriate. For diagnostic or research applications, various mammals are suitable subjects, including rodents (eg, mice, rats, hamsters), rabbits, pigs such as primates and inbred pigs, and the like. In addition, for in-vivro applications such as in-vivro diagnostic and research applications, the body fluids and cell samples of the above subjects may be blood, urine or tissue samples, or veterinary samples of mammals, especially primates such as humans. Suitable for use such as blood urine or tissue samples of animals mentioned for use.

The radiopharmaceutical according to the present disclosure may be a positron-radiated gallium-68 complex, which, when used in combination with the ⁶⁸ Ge / ⁶⁸ Ga parent / daughter radionuclide generator system, enables PET imaging studies and for radionuclide generation. It will prevent the expenses related to the operation of the in-house cyclotron.

The complex is formulated into an aqueous solution suitable for intravenous administration using standard techniques for the preparation of parenteral diagnostics. The aqueous solution of this complex can be sterilized, for example, by passing it through a commercially available 0.2 micron filter. The complex is generally administered intravenously in an amount effective to give the tissue concentration of the radionuclide complex sufficient to obtain the photon (gamma / positron) bundles needed to image the tissue. The dose level of any given complex of the present disclosure to achieve acceptable tissue imaging depends on its particular biodistribution and the sensitivity of the tissue imaging device. Effective dose levels can be determined by routine experimentation. They generally range from about 5 to about 30 millicuries. If the complex is a gallium-68 complex for PET imaging of myocardial tissue, suitable photon bundles can be obtained by intravenous administration of the complex from about 5 to about 30 millicuries.

As used herein, the term "amino acid" includes naturally occurring amino acids and non-natural amino acids. Naturally occurring amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamine, glutamic acid, glycine, histidine, hydroxyproline, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, treonine, Refers to amino acids known to be used to form the basic constituents of proteins, including tryptophan, tyrosine, valine and combinations thereof. Examples of unnatural amino acids are: unnatural analogs of tyrosine amino acids; unnatural analogs of glutamine amino acids; unnatural analogs of phenylalanine amino acids; unnatural analogs of serine amino acids; unnatural analogs of treonine amino acids. Amino acids of: alkyl, aryl, acyl, azide, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynl, ether, thiol, sulfonyl, sereno, ester, thioic acid, borate, boronate, phospho, phosphono, Amino acids substituted with phosphine, heterocyclic, enon, imine, aldehyde, hydroxylamine, ketone or amino, or any combination thereof; amino acids with photoactivated cross-linking agents; spin-labeled amino acids; fluorescent amino acids; Amino acids with novel functional groups; amino acids that interact covalently or non-covalently with another molecule; metal-bound amino acids; metal-containing amino acids; radioactive amino acids; photocaged and / or photoisomerizable Amino acids; Biotin or biotin analog-containing amino acids; Glycosylated or carbohydrate-modified amino acids; Keto-containing amino acids; Amino acids containing polyethylene glycol or polyether; Heavy atom-substituted amino acids; Chemically cleavable or photo-cleavable amino acids; Amino acids with extended side chains; Amino acids containing toxic groups; Sugar-substituted amino acids, such as sugar-substituted serines; Carbon-linked sugar-containing amino acids; Amino acids with oxidative reduction activity; α-hydroxy containing Acids; amino thioic acid-containing amino acids; α, α disubstituted amino acids; β-amino acids; and cyclic amino acids other than proline.

のことを指し、Ｒ^３０は、アルキル、シクロアルキル、アリール、（シクロアルキル）アルキルまたはアリールアルキルであり、そのいずれも任意選択で置換される。アシル基は、例えば、Ｃ_１～６アルキルカルボニル（例えばアセチルなど）、アリールカルボニル（例えばベンゾイルなど）、レブリノイルまたはピバロイルであることができる。別の実施形態では、アシル基はベンゾイルである。 The term "alkanoyl" as used herein has the following structure:

R ³⁰ is an alkyl, cycloalkyl, aryl, (cycloalkyl) alkyl or arylalkyl, all of which are optionally substituted. The acyl group can be, for example, _a C1-6 alkylcarbonyl (eg, acetyl), arylcarbonyl (eg, benzoyl, etc.), lebrinoyl or pivaloyl. In another embodiment, the acyl group is a benzoyl.

As used herein, the term "alkyl" includes both branched and linear saturated aliphatic hydrocarbon groups with a specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl and s-pentyl. Preferred alkyl groups are C ₁ to C ₁₀ alkyl groups. Typical C _1-10 alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl, isopropyl. , Se-butyl, tert-butyl, isobutyl, isopentyl, neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl , 3-Methylpentyl, 4-Methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl , 2,3-Dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3 Included are dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl and 3,3-dimethylheptyl. In one embodiment, the useful alkyl group is selected from a straight chain C _1-6 alkyl group and a branched chain C _3-6 alkyl group. Among them, typical C _1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 3-pentyl and hexyl. In one embodiment, the useful alkyl group is selected from a straight chain C _2-6 alkyl group and a branched chain C _3-6 alkyl group. Among them, typical C2-6 alkyl groups include ethyl, propyl, isopropyl, butyl, sec _- butyl, tert-butyl, isobutyl, pentyl, 3-pentyl and hexyl. In one embodiment, the useful alkyl group is selected from a straight chain C _1-4 alkyl group and a branched chain C _3-4 alkyl group. Typical C _1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl.

As used herein, the term "cycloalkyl" includes saturated ring groups having a specified number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkyl groups generally have 3 to about 12 ring atoms. In one embodiment, cycloalkyl has one or two rings. In another embodiment, the cycloalkyl is C ₃ to C ₈ cycloalkyl. In another embodiment, the cycloalkyl is C _3-7 cycloalkyl. In another embodiment, the cycloalkyl is C _3-6 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin and adamantyl.

As used herein, the term "heterocycloalkyl" refers to a saturated heterocyclic alkyl group.

As used herein, the term "aryl" includes C _6-14 aryls, in particular C _6-10 aryls. Typical C _6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azurenyl, biphenyl, biphenylenyl and fluorenyl groups, more preferably phenyl, naphthyl and biphenyl groups.

As used herein, the term "heteroaryl" or "heterocyclic aromatic" has 5-14 ring atoms with 6, 10 or 14 π electrons shared in a cyclic configuration. A group containing a carbon atom and one, two or three oxygen, nitrogen or sulfur heteroatoms, or four nitrogen atoms. In one embodiment, the heteroaryl group is a 5- to 10-membered ring heteroaryl group. Examples of heteroaryl groups include thienyl, benzo [b] thienyl, naphtho [2,3-b] thienyl, thiantrenyl, frill, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl. , 2H-pyrrolill, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, isoindrill, 3H-indrill, indrill, indazolyl, prynyl, isoquinolyl, quinolyl, phthalazinyl, naphthyldinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl , Β-Carborinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isooxazolyl, frazanyl and phenoxadinyl. Typical heteroaryl groups include thienyl (eg, thien-2-yl and thien-3-yl), frills (eg, 2-furyl and 3-frill), pyrrolyl (eg, pyrrole-1-yl, 1H). -Pyrrole-2-yl and 1H-pyrrole-3-yl), imidazolyl (eg, imidazole-1-yl, 1H-imidazole-2-yl and 1H-imidazole-4-yl), tetrazolyl (eg, tetrazol-1). -Il and tetrazol-5-yl), pyrazolyl (eg, 1H-pyrazole-3-yl, 1H-pyrazole-4-yl and 1H-pyrazole-5-yl), pyridyl (eg, pyridine-2-yl, pyridine) -3-yl and Pyridine-4-yl), pyrimidinyl (eg, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidine-5-yl and pyrimidin-5-yl), thiazolyl (eg, thiazol2-yl, etc.) Thiazol-4-yl and thiazol-5-yl), isothiazolyl (eg, isothiazole-3-yl, isothazole-4-yl and isothiazole-5-yl), oxazolyl (eg, oxazole-2-yl, oxazole). -4-yl and oxazole-5-yl) and isooxazolyl (eg, isooxazole-3-yl, isooxazole-4-yl and isooxazole-5-yl). The 5-membered heteroaryl can contain up to 4 heteroatoms. The 6-membered ring heteroaryl can contain up to 3 heteroatoms. Each heteroatom is independently selected from nitrogen, oxygen and sulfur.

Suitable carboxylic acid protecting groups are well known, for example, Wuts, P.G.M. and Greene, T.W., Greene's Protective Groups in Organic Synthesis, 4th Edition, pp. 16-430 (J. Includes any suitable carboxylic acid protecting group disclosed in Wiley & Sons, 2007). Technicians are familiar with the selection, binding and cleavage of protecting groups, many different protecting groups are known to those of skill in the art, and the suitability of one or another protecting group is planned for the particular synthesis. Recognize that it depends on the scheme. Suitable carboxylic acid protecting groups include, for example, methyl esters, t-butyl esters, benzyl esters and allyl esters.

Materials and Methods for Synthesis In general all reagents and solvents were purchased commercially (Aldrich, Acros or Alfa Inc.) and used without further purification unless otherwise stated. The solvent was dried by a molecular sieving system (Pure Solve Solvent Purification System; Innovative Technology, Inc.). ¹ H and ¹³ C NMR spectra were recorded on a Bruker Availability spectrometer at 400 MHz and 100 MHz, respectively, and an NMR solvent was referenced as shown. The chemical shift is reported in ppm (δ) with the coupling constant J at Hz. Multiplicity is defined by single line (s), double line (d), triple line (t), broad (br) and multiple line (m). High resolution mass spectrometry (HRMS) data were obtained with an Agilent (Santa Clara, CA) G3250AA LC / MSD TOF system. Thin layer chromatography (TLC) analysis was performed using Merck (Darmstadt, Germany) silica gel 60 F ₂₅₄ plates. In general, crude compounds were purified by flash column chromatography (FC) packed with silica gel (Aldrich). High performance liquid chromatography (HPLC) was performed on an Agilent 1100 series system. ⁶⁸ Ga radioactivity was measured with a gamma counter (Cobra II automatic gamma counter, Perkin-Elmer). Reactions of non-radioactive compounds were monitored by thin layer chromatography (TLC) analysis on precoated plates of silica gel 60F ₂₅₄ . An aqueous solution of [ ⁶⁸ Ga] GaCl ₃ was obtained from a ⁶⁸ Ge / ⁶⁸ Ga generator (Radiomedix Inc.). Solid-phase extraction cartridges (SEP Pak® Light QMA, Oasis® HLB 3cc) were obtained from Waters (Milford, MA, USA).

Compounds 4, 7, 17, 18, 26, 27, 29, 38, 42, and 51, all having a urea-Glu group (Glu-NH-CO-NH-), are as described in the sections below. Prepared. Note that PSMA-11 and MIP-1095 are known PSMA contrast agents and are presented as positive controls for binding to PSMA.

The preparation of Intermediate Compound 2 is described in US Patent Application Publication No. 2017/0189568, which is incorporated herein by reference in its entirety, based on the following chemical reaction (Scheme 8).

The preparation of compound 4 was based on the following chemical reaction (Scheme 9). Compounds 1 and 2 were synthesized according to a known method [5].

The preparation of compound 7 was based on the following chemical reaction (Scheme 10).

(Example 1)
4-(7-(5-((2-(((S) -2-((((4S, 11S, 15S) -4-benzyl-11,15-bis (tert-butoxycarbonyl) -20) -20 , 20-dimethyl-2,5,13,18-tetraoxo-19-oxa-3,6,12,14-tetraazahenicosyl) oxy) phenyl) -1-carboxyethyl) amino) -2-oxoethyl) Amino) -1- (tert-butoxy) -1,5-dioxopentan-2-yl) -4,10-bis (2- (tert-butoxy) -2-oxoethyl) -1,4,7,10 -Tetraazacyclododecane-1-yl) -5- (tert-butoxy) -5-oxopentanoic acid (3)
N, N-diisopropylethylamine (DIPEA, 49 mg, 0.38 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 32.7 mg, 0) in a solution of 2 (124 mg, 0.129 mmol) in 5 mL of DMF. .19 mmol), N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDC, 37 mg, 0.19 mmol), and 1 (100 mg, 0.129 mmol) were added at 0 ° C. The mixture was stirred at room temperature overnight and then 30 mL of EtOAc was added to the reaction mixture. It was then washed with H2O (10 mL x 2) and brine (10 mL), dried over 00544 and filtered. The filtrate was concentrated and the residue was purified by FC (DCM / MeOH / NH4OH = 90/9/1) to give 40 mg of 3 as a colorless oil (yield: 17.6%).

(Example 2)
(4S, 11S, 15S) -4-benzyl-1- (4-((2S) -2- (2- (4- (4,10-bis (carboxymethyl) -7- (1,3-dicarboxy)) Propyl) -1,4,7,10-tetraazacyclododecane-1-yl) -4-carboxybutaneamide) acetamide) -2-carboxyethyl) phenoxy) -2,5,13-trioxo-3,6 12,14-Tetraazaheptadecane-11,15,17-tricarboxylic acid (4)
A solution of 3 (20 mg, 0.011 mmol) in 1 mL of TFA was stirred at room temperature for 5 hours. The reaction mixture was vacuum evaporated and the residue was recrystallized from ether / EtOH. The resulting white solid was dissolved in 1 mL of MeOH and purified by half-taken HPLC to give 5 as a yellow oil (yield: 10 mg, 71.3%): ¹ HNMR (400 MHz, MeOD). δ: 7.16-7.29 (m, 7H), 6.85-6.89 (m, 2H), 4.65-4.67 (m, 2H), 4.45-4.55 (m, 2H), 4.31-4.34 (m, 2H), 4.23-4.24 (m, 4H), 2.95-3.92 (m, 25 H), 2.62-2.70 (m, 4H), 2.40-2.45 (m, 2H), 1.62-2.17 (m, 8H), 1.36-1.47 (m, 4H) ); HRMS C ₅₆ H ₇₉ N ₁₀ O ₂₄ (M + H) ⁺ calculated value, 1275.5269; measured value 1275.5338.

(Example 3)
N- (2- (2- (2-Aminoethoxy) ethoxy) ethyl) -4- (4-iodophenyl) butaneamide (5)
NHS (69 mg, 0.6 mmol) and DCC (125 mg, 0.6 mmol) were added to a solution of 4- (p-iodophenyl) butyric acid (145 mg, 0.5 mmol) in 5 mL of DCM. The reaction was stirred at room temperature for 2 hours. 20 mL of THF was then added to the mixture, followed by the addition of ethylene glycol bis (2-aminoethyl) ether (210 mg, 1.5 mmol). The reaction mixture was then stirred at room temperature overnight, the solvent was removed and the residue was purified by FC (DCM / MeOH / NH ₄ OH = 90/9/1) to give 120 mg of 5 as a colorless oil. (Yield: 57.1%). ^{1 1} HNMR (400 MHz, MeOD) δ: 7.61 (d, 2H, J = 8.0 Hz), 6.96 (d, 2H, J = 8.0 Hz), 6.24 (br S, 1H), 3.52-3.60 (m, 8H) , 3.45-3.49 (m, 2H), 2.87-2.89 (m, 2H), 2.60-2.64 (m, 2H), 2.17-2.21 (m, 2H), 1.94-1.98 (m, 2H).

(Example 4)
(2S) -3- (4-(((4S, 11S, 15S) -4-benzyl-11,15-bis (tert-butoxycarbonyl) -20,20-dimethyl-2,5,13,18-tetraoxo) -19-Oxa-3,6,12,14-tetraazahenicosyl) oxy) phenyl) -2-(2-(4- (4,10-bis (2- (tert-butoxy) -2-oxoethyl) ) -7- (22- (4-Iodophenyl) -2,2-dimethyl-4,8,19-trioxo-3,12,15-trioxa-9,18-diazadocosan-5-yl) -1,4 , 7,10-Tetraazacyclododecane-1-yl) -5- (tert-butoxy) -5-oxopentaneamide) acetamide) propanoic acid (6)
N, N-diisopropylethylamine (DIPEA, 3.9 mg, 0.07 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 2 mg, 0) in a solution of 3 (10 mg, 0.01 mmol) in 5 mL of DMF. .015 mmol), N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDC 2.9 mg, 0.015 mmol), and 5 (4.2 mg, 0.01 mmol) were added at 0 ° C. The mixture was stirred at room temperature overnight and then 30 mL of EtOAc was added to the reaction mixture. It was then washed with _H2O (10 mL x 2) and brine (10 mL), dried with _Л4 and filtered. The filtrate was concentrated and the residue was purified by FC (DCM / MeOH / NH ₄ OH = 90/9/1) to give 20 mg of 6 as a colorless oil (yield: 92%).

(Example 5)
(4S, 11S, 15S) -4-benzyl-1- (4-((2S) -2-carboxy-2- (2- (4-carboxy-4- (7- (1-carboxy-18- (4)) -Iodophenyl) -4,15-dioxo-8,11-dioxa-5,14-diazaoctadecyl) -4,10-bis (carboxymethyl) -1,4,7,10-tetraazacyclododecane-1 -Il) butaneamide) acetamide) ethyl) phenoxy) -2,5,13-trioxo-3,6,12,14-tetraazaheptadecan-11,15,17-tricarboxylic acid (7)
A solution of 6 (20 mg, 0.0092 mmol) in 1 mL of TFA was stirred at room temperature for 5 hours. The reaction mixture was vacuum evaporated and the residue was recrystallized from ether / EtOH. The resulting white solid was dissolved in 1 mL of MeOH and purified by half-taken HPLC to give 7 as a yellow oil (yield: 12 mg, 77.8%): 1HNMR (400 MHz, MeOD) δ. : 7.62 (d, 2H, J = 7.6 Hz), 7.16-7.29 (m, 7H), 7.01 (d, 2H, J = 7.6 Hz), 6.88 (m, 2H), 4.66-4.67 (m, 2H), 4.45-4.55 (m, 2H), 4.32 (m, 2H), 4.24 (m, 2H), 3.00-3.98 (m, 35H), 2.59-2.67 (m, 8H), 2.43 (m, 2H), 2.20- 2.36 (m, 2H), 1.64-2.16 (m, 10H), 1.35-1.54 (m, 4H); HRMS C72H102IN12O26 (M + H) + calculated value, 1677.6073; measured value 1677.6157.

The preparation of compounds 17 and 18 was based on the following chemical reaction (Scheme 11).

Di-tert-butyl (((S) -6-((S) -2-((S) -2-amino-5- (tert-butoxy) -5-oxopentane amide) -3-phenylpropanamide)) -1- (tert-butoxy) -1-oxohexane-2-yl) carbamoyl) -L-glutamate (11).
N, N-diisopropylethylamine (DIPEA, 267 mg, 2.07 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 175 mg, 1 mmol), in a solution of 10 (440 mg, 0.69 mmol) in 10 mL of DMF. N- (3-Didimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDC, 191 mg, 1 mmol) and Fmoc-Glu (OtBu) -OH (300 mg, 0.69 mmol) were added at 0 ° C. After stirring overnight at room temperature, 1 mL of piperidine was added to the mixture and maintained at room temperature for 2 hours. 50 mL of EtOAc was added to the reaction mixture. It was then washed with _H2O (20 mL x 2) and brine (20 mL), dried with _Л4 and filtered. The filtrate was concentrated and the residue was purified by FC (DCM / MeOH / NH ₄ OH = 90/9/1) to give 366 mg of 11 as a colorless oil (yield: 64.8%). HRMS C ₄₂ H ₇₀ N ₅ O ₁₁ (M + H) ⁺ calculated value, 820.5072; measured value 820.5103.

Di-tert-butyl (((S) -6-((S) -2-((S) -2-((S) -2-amino-5- (tert-butoxy) -5-oxopentane amide)) -5- (tert-butoxy) -5-oxopentaneamide) -3-phenylpropanamide) -1- (tert-butoxy) -1-oxohexane-2-yl) carbamoyl) -L-glutamate (12).
Compound 12 was added to 11 (266 mg, 0.32 mmol), N, N-diisopropylethylamine (DIPEA, 123 mg, 0.96 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 81 mg, 0.48 mmol), N- ( Same as described for compound 11 from 3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (EDC, 91 mg, 0.48 mmol), and Fmoc-Glu (OtBu) -OH (143 mg, 0.32 mmol). Prepared according to the procedure. Compound 12: 159 mg (yield: 49.4%). HRMS C ₅₁ H ₈₅ N ₆ O ₁₄ (M + H) ⁺ calculated value, 1005.6124; measured value 1005.6087.

Di-tert-butyl (((S) -1- (tert-butoxy) -6-((S) -2-((S) -5- (tert-butoxy) -5-oxo-2- (4-) (Tributylstannyl) benzamide) pentaneamide) -3-phenylpropanamide) -1-oxohexane-2-yl) carbamoyl) -L-glutamate (13).
DIPEA (10 mg, 0.08 mmol) and 9 (37 mg, 0.06 mmol) were added to a solution of 11 (43 mg, 0.05 mmol) in 10 mL DMF at 0 ° C. The mixture was stirred at room temperature for 5 hours and the solvent was removed in vacuo. The residue was purified by FC (DCM / MeOH / NH ₄ OH = 95/5 / 0.5) to give 17.7 mg of 13 as a colorless oil (yield: 28.1%). ^{1 1} HNMR (400 MHz, CDCl ₃ ) δ: 8.03 (d, 1H, J = 4.4 Hz), 7.76 (d, 2H, J = 6.4 Hz), 7.48-7.59 (m, 2H), 7.15 (s, 4H) , 7.09 (s, 1H), 6.91-6.97 (m, 2H), 5.99 (d, 1H, J = 7.6 Hz), 5.79 (d, 1H, J = 8.4 Hz), 5.31 (s, 1H), 4.53- 4.60 (m, 2H), 4.29-4.34 (m, 2H), 3.06-3.35 (m, 4H), 2.30-2.37 (m, 4H), 2.04-2.09 (m, 3H), 1.79-1.87 (m, 1H) ), 1.53-1.59 (m, 6H), 1.42-1.45 (m, 40H), 1.29-1.37 (m, 6H), 1.08-1.12 (m, 6H), 0.88-0.91 (m, 9H); HRMS C ₆₁ H ₉₉ N ₅ NaO ₁₂ Sn (M + Na) ⁺ calculated value, 1236.6210; measured value 1236.6248.

Di-tert-butyl (((S) -1- (tert-butoxy) -6-((S) -2-((S) -5- (tert-butoxy) -2-((S) -5-) (Tert-Butoxy) -5-oxo-2- (4- (tributylstannyl) benzamide) pentane amide) -5-oxopentane amide) -3-phenylpropanamide) -1-oxohexane-2-yl) carbamoyl ) -L-Glutamate (14).
DIPEA (77 mg, 0.06 mmol) and 9 (24 mg, 0.048 mmol) were added to a solution of 12 (40 mg, 0.04 mmol) in 10 mL of DCM at 0 ° C. The mixture was stirred at room temperature overnight and the solvent was evacuated. The residue was purified by FC (DCM / MeOH / NH ₄ OH = 95/5 / 0.5) to give 25.6 mg of 14 as a colorless oil (yield 45.8%). ^{1 1} HNMR (400 MHz, MeOD) δ: 8.82 (d, 1H, J = 3.6 Hz), 8.70 (d, 1H, J = 6.4 Hz), 7.92 (d, 2H, J = 6.4 Hz), 7.51-7.62 ( m, 3H), 7.11-7.17 (m, 5H), 6.86 (s, 1H), 6.36 (d, 1H, J = 8.0 Hz), 5.53 (d, 1H, J = 7.2 Hz), 4.80-4.84 (m) , 1H), 4.30-4.45 (m, 4H), 3.62-3.65 (m, 1H), 3.37-3.39 (m, 1H), 3.20-3.25 (m, 1H), 2.97-3.03 (m, 1H), 2.65 -2.69 (m, 1H), 2.50-2.57 (m, 1H), 2.24-2.30 (m, 5H), 2.03-2.08 (m, 2H), 1.62-1.85 (m, 5H), 1.38-1.56 (m, 5H) 55H), 1.07-1.11 (m, 6H), 0.88-0.91 (m, 9H); HRMS C ₇₀ H ₁₁₄ N ₆ NaO ₁₅ Sn (M + Na) ⁺ calculated value, 1421.7262; measured value 1421.7242.

Di-tert-butyl (((S) -1- (tert-butoxy) -6-((S) -2-((S) -5- (tert-butoxy) -2- (4-iodobenzamide)- 5-oxopentane amide) -3-phenylpropaneamide) -1-oxohexane-2-yl) carbamoyl) -L-glutamate (15).
Compound 15 was prepared from 12 (37 mg, 0.045 mmol), DIPEA (9 mg, 0.07 mmol), and 8 (19 mg, 0.054 mmol) according to the same procedure described for compound 13. Compound 15: 24 mg (yield: 50.7%). ^{1 1} HNMR (400 MHz, CDCl ₃ ) δ: 8.12 (d, 1H, J = 5.6 Hz), 7.77 (d, 2H, J = 7.6 Hz), 7.57 (d, 2H, J = 7.6 Hz), 7.09-7.16 (m, 6H), 6.94 (s, 1H), 5.99 (d, 1H, J = 4.8Hz), 5.83 (d, 1H, J = 8.0 Hz), 4.53-4.61 (m, 2H), 4.15-4.36 ( m, 2H), 3.39 (d, 1H, J = 7.6 Hz), 3.01-3.22 (m, 2H), 2.98-3.04 (m, 1Hz), 2.28-2.41 (m, 4H), 2.00-2.07 (m, 3H), 1.50-1.85 (m, 3H), 1.42-1.45 (m, 40H); HRMS C ₄₉ H ₇₃ IN ₅ O ₁₂ (M + H) ⁺ calculated value, 1050.4300; measured value 1050.4326.

Di-tert-butyl (((S) -1- (tert-butoxy) -6-((S) -2-((S) -5- (tert-butoxy) -2-((S) -5-) (Tert-Butoxy) -2- (4-iodobenzamide) -5-oxopentane amide) -5-oxopentane amide) -3-phenylpropanamide) -1-oxohexane-2-yl) carbamoyl) -L- Glutamate (16).
Compound 16 was prepared from 12 (40 mg, 0.04 mmol), DIPEA (26 mg, 0.048 mmol), and 8 (17 mg, 0.048 mmol) according to the same procedure described for compound 13. Compound 16: 40 mg (yield: 80.1%). ^{1 1} HNMR (400 MHz, MeOD) δ: 8.87 (d, 1H, J = 3.6 Hz), 8.81 (d, 1H, J = 6.4 Hz), 7.82 (d, 2H, J = 8.4 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.50 (d, 1H, J = 8.8 Hz), 7.11-7.17 (m, 5H), 6.92 (s, 1H), 6.31 (d, 1H, J = 8.4 Hz), 5.52 ( d, 1H, J = 7.6 Hz), 4.72-4.83 (m, 1H), 4.31-4.42 (m, 4H), 3.59-3.63 (m, 1H), 3.32-3.40 (m, 1H), 3.20-3.25 ( m, 1H), 2.94-3.01 (m, 1H), 2.56-2.65 (m, 1H), 2.45-2.50 (m, 1H), 2.10-2.32 (m, 5H), 2.01-2.08 (m, 2H), 1.62-1.88 (m, 5H), 1.41-1.56 (m, 49H); HRMS C ₅₈ H ₈₈ IN ₆ O ₁₅ (M + H) ⁺ calculated value, 1235.5352; measured value 1235.5422.

(((S) -1-carboxy-5-((S) -2-((S) -4-carboxy-2- (4-iodobenzamide) butaneamide) -3-phenylpropanamide) pentyl) carbamoyl)- L-Glutamic acid (17).
Compound 17 was prepared from the addition of 15 (17 mg, 0.016 mmol) to 1 mL of TFA according to the same procedure described for compound 4. Compound 17: 8.6 mg (yield: 64.2%). ^{1 1} HNMR (400 MHz, MeOD) δ: 7.86 (d, 2H, J = 7.6 Hz), 7.61 (d, 2H, J = 8.0 Hz), 7.18 (s, 4H), 7.15 (s, 1H), 4.54- 4.57 (m, 1H), 4.46-4.49 (m, 1H), 4.21-4.30 (m, 2H), 3.58-3.60 (m, 2H), 3.47-3.52 (m, 1H), 3.11-3.16 (m, 3H) ), 2.95-3.00 (m, 1H), 2.34-2.41 (m, 4H), 1.99-2.17 (m, 4H), 1.75-1.77 (m, 1H), 1.60-1.64 (m, 1H), 1.43-1.45 (m, 2H), 1.12-1.27 (m, 2H); HRMS C ₃₃ H ₄₁ IN ₅ O ₁₂ (M + H) ⁺ calculated value, 826.1796; measured value 826.1755.

(((S) -1-carboxy-5-((S) -2-((S) -4-carboxy-2-((S) -4-carboxy-2- (4-iodobenzamide) butaneamide) butaneamide) Butaneamide) ) -3-Phenylpropaneamide) Pentyl) Carbamic acid) -L-Glutamic acid (18).
Compound 18 was prepared from the addition of 16 (38 mg, 0.031 mmol) to 1 mL of TFA according to the same procedure described for compound 4. Compound 18: 10.1 mg (yield: 34.1%). ^{1 1} HNMR (400 MHz, MeOD) δ: 8.51 (d, 1H, J = 6.4 Hz), 7.98 (d, 1H, J = 8.4 Hz), 7.86 (d, 2H, J = 8.4 Hz), 7.71 (s, 1H), 7.66 (d, 2H, J = 8.4 Hz), 7.16-7.22 (m, 5H), 4.54-4.58 (m, 1H), 4.45-4.48 (m, 1H), 4.26-4.31 (m, 3H) , 3.15-3.21 (m, 3H), 3.15-3.21 (m, 1H), 2.49-2.52 (m, 2H), 2.31-2.41 (m, 2H), 2.25-2.28 (m, 1H), 2.08-2.19 ( m, 4H), 1.77-1.97 (m, 4H), 1.62-1.68 (m, 1H), 1.44-1.49 (m, 2H), 1.34-1.39 (m, 2H); HRMS C ₃₈ H ₄₈ IN ₆ O ₁₅ (M + H) ⁺ calculated value, 955.2222; measured value 955.2273.

The preparation of compounds 26 and 27 was based on the following chemical reaction (Scheme 12).

Di-tert-butyl (((S) -6-((S) -2-(2-(4-((S) -2-((S) -2-amino-5- (tert-butoxy)-)- 5-oxopentane amide) -3- (tert-butoxy) -3-oxopropyl) phenoxy) acetamide) -3-phenylpropanamide) -1- (tert-butoxy) -1-oxohexane-2-yl) carbamoyl ) -L-Glutamate (20).
Compound 20 was added to 19 (455 mg, 0.5 mmol), DIPEA (193 mg, 1.5 mmol), HOBt (127 mg, 0.75 mmol), EDC (142 mg, 0.75 mmol), and Fmoc-Glu (OtBu) -OH ( From 221 mg, 0.5 mmol), prepared according to the same procedure described for compound 11. Compound 20: 361 mg (yield: 65.8%). HRMS C ₅₇ H ₈₉ N ₆ O ₁₅ (M + H) ⁺ calculated value, 1097.6386; measured value 1097.6399.

Di-tert-butyl (((S) -6-((S) -2-(2-(4-((S) -2-((S) -2-((S) -2-amino-5) -(Tert-Butyloxy) -5-oxopentanamide) -5- (tert-butoxy) -5-oxopentanamide) -3- (tert-butoxy) -3-oxopropyl) phenoxy) acetamide) -3-phenyl Propanamide) -1- (tert-butoxy) -1-oxohexane-2-yl) carbamoyl) -L-glutamate (21).
Compound 21 was added to 20 (220 mg, 0.2 mmol), DIPEA, (78 mg, 0.6 mmol), HOBt (51 mg, 0.3 mmol), EDC (57 mg, 0.3 mmol), and Fmoc-Glu (OtBu) -OH. Prepared from (88 mg, 0.2 mmol) according to the same procedure described for compound 11. Compound 21: 156 mg (yield: 60.8%). HRMS C ₆₆ H ₁₀₄ N ₇ O ₁₈ (M + H) ⁺ calculated value, 1282.7438; measured value 1282.7511.

Di-tert-butyl (((S) -1- (tert-butoxy) -6-((S) -2-(2-(4-((S) -3- (tert-butoxy) -2-( (S) -5- (tert-butoxy) -5-oxo-2- (4- (tributylstannyl) benzamide) pentaneamide) -3-oxopropyl) phenoxy) acetamide) -3-phenylpropaneamide) -1 -Oxohexane-2-yl) carbamoyl) -L-glutamate (22).
Compound 22 was prepared from 20 (76 mg, 0.07 mmol), DIPEA (27 mg, 0.21 mmol), and 9 (69.4 mg, 0.14 mmol) according to the same procedure described for compound 13. Compound 22: 33.6 mg (yield: 48.0%). ¹ HNMR (400 MHz, CD ₂ Cl ₂ ) δ: 7.70 (d, 2H, J = 6.8 Hz), 7.51 (d, 2H, J = 7.2 Hz), 7.38 (d, 2H, J = 6.4 Hz), 7.62 -7.30 (m, 2H), 7.19-7.23 (m, 1H), 6.88 (d, 2H, J = 7.6 Hz), 6.54 (d, 2H, J = 7.6 Hz), 5.55 (d, 1H, J = 8.4) Hz), 4.76 (s, 1H), 4.48 (s, 1H), 4.25 (s, 1H), 3.16-3.40 (m, 5H), 2.97-3.08 (m, 2H), 2.25-2.47 (m, 5H) , 2.10-2.17 (m, 3H), 1.87-1.95 (m, 2H), 1.51-1.57 (m, 13H), 1.43 (d, 25H, J = 11.2 Hz), 1.27-1.36 (m, 18H), 1.12 -1.27 (m, 7H), 1.08-1.12 (m, 6H), 0.87-0.92 (m, 9H); HRMS C ₇₆ H ₁₁₈ N ₆ NaO ₁₆ Sn (M + Na) ⁺ calculated value, 1513.7524; measured value 1513.7674.

Di-tert-butyl (((S) -1- (tert-butoxy) -6-((S) -2-(2-(4-((S) -3- (tert-butoxy) -2-( (S) -5- (tert-butoxy) -2-((S) -5- (tert-butoxy) -5-oxo-2- (4- (tributylstannyl) benzamide) pentanamide) -5-oxo Pentanamide) -3-oxopropyl) phenoxy) acetamide) -3-phenylpropanamide) -1-oxohexane-2-yl) carbamoyl) -L-glutamate (23).
Compound 23 was prepared from 21 (50 mg, 0.04 mmol), DIPEA (6 mg, 0.048 mmol), and 9 (13.8 mg, 0.04 mmol) according to the same procedure described for compound 13. Compound 23: 35 mg (yield: 57.8%). ^{1 1} HNMR (400 MHz, CDCl ₃ ) δ: 7.81 (d, 2H, J = 6.4 Hz), 7.54-7.56 (m, 3H), 7.32-7.34 (m, 1H), 7.19-7.28 (m, 5H), 7.09-7.11 (m, 3H), 6.76-6.78 (m, 3H), 6.08 (s, 1H), 5.69 (d, 1H, J = 7.2 Hz), 4.80-4.82 (m, 1H), 4.63-4.69 ( m, 2H), 4.36-4.51 (m, 5H), 3.37-3.39 (m, 1H), 2.96-3.12 (m, 5H), 2.52-2.56 (m, 1H), 2.32-2.43 (m, 5H), 2.01-2.20 (m, 6H), 1.75-1.84 (m, 2H), 1.28-1.55 (m, 64H), 1.07-1.11 (m, 6H), 0.88-0.92 (m, 9H); HRMS C ₈₅ H ₁₃₃ NaN ₇ O ₁₉ Sn (M + H) ⁺ calculated value, 1698.8576; measured value 1698.8774.

Di-tert-butyl (((S) -1- (tert-butoxy) -6-((S) -2-(2-(4-((S) -3- (tert-butoxy) -2-( (S) -5- (tert-butoxy) -2- (4-iodobenzamide) -5-oxopentane amide) -3-oxopropyl) phenoxy) acetamide) -3-phenylpropaneamide) -1-oxohexane- 2-Il) Carbamoyl) -L-glutamate (24).
Compound 24 was prepared from 20 (67 mg, 0.06 mmol), DIPEA (24 mg, 0.19 mmol), and 8 (33 mg, 0.096 mmol) according to the same procedure described for compound 13. Compound 24: 41.4 mg (yield: 50.6%). ¹ HNMR (400 MHz, CD ₂ Cl ₂ ) δ: 7.76 (d, 2H, J = 8.0 Hz), 7.52 (d, 2H, J = 7.6 Hz), 7.22-7.32 (m, 5H), 6.91 (d, 2H, J = 7.6 Hz), 6.57 (d, 2H, J = 7.2 Hz), 5.10-5.18 (m, 2H), 4.73 (s, 1H), 4.44 (s, 1H), 4.21 (s, 1H), 4.07 (s, 1H), 3.13-3.34 (m, 5H), 2.93-3.05 (m, 2H), 2.25-2.48 (m, 5H), 2.00-2.13 (m, 3H), 1.84-1.90 (m, 2H) ), 1.32-1.49 (m, 49H); HRMS C ₆₄ H ₉₂ IN ₆ O ₁₆ (M + H) ⁺ calculated value, 1327.5614; measured value 1327.5533.

Di-tert-butyl (((S) -1- (tert-butoxy) -6-((S) -2-(2-(4-((S) -3- (tert-butoxy) -2-( (S) -5- (tert-butoxy) -2-((S) -5- (tert-butoxy) -2- (4-iodobenzamide) -5-oxopentanamide) -5-oxopentanamide)- 3-oxopropyl) phenoxy) acetamide) -3-phenylpropanamide) -1-oxohexane-2-yl) carbamoyl) -L-glutamate (25).
Compound 25 was prepared from 21 (50 mg, 0.04 mmol), DIPEA (6 mg, 0.048 mmol), and 8 (23 mg, 0.04 mmol) according to the same procedure described for compound 13. Compound 25: 12.5 mg (yield: 18.6%). ^{1 1} HNMR (400 MHz, CDCl3) δ: 7.85 (d, 2H, J = 8.4 Hz), 7.64-7.70 (m, 3H), 7.17-7.26 (m, 5H), 6.98-7.09 (m, 3H), 6.72 (d, 2H, J = 7.6 Hz), 6.28 (s, 1H), 5.70 (s, 1H), 4.93-4.95 (m, 1H), 4.66-4.67 (m, 1H), 4.57-4.58 (m, 2H) ), 4.14-4.37 (m, 5H), 3.48-3.63 (m, 1H), 3.35-3.38 (m, 1H), 3.02-3.13 (m, 5H), 2.40-2.52 (m, 2H), 2.26-2.36 (m, 6H), 1.85-2.16 (m, 6H), 1.59-1.69 (m, 2H), 1.41-1.50 (m, 58H); HRMS C _{73H 107} IN ₇ O ₁₉ (M + H) ⁺ calculated value, 1535.6564; measured value 15356.6607.

(((S) -1-carboxy-5-((S) -2-(2-(4-((S) -2-carboxy-2-((S) -4-carboxy-2- (4-) Iodine benzamide) butane amide) ethyl) phenoxy) acetamide) -3-phenylpropanamide) pentyl) carbamoyl) -L-glutamic acid (26).
Compound 26 was prepared from the addition of 24 (41 mg, 0.03 mmol) to 1 mL of TFA according to the same procedure described for compound 4. Compound 26: 16.0 mg (yield: 49.4%). ¹ HNMR (400 MHz, MeOD) δ: 7.82 (d, 2H, J = 7.2 Hz), 7.55 (d, 2H, J = 7.6 Hz), 7.13-7.25 (m, 7H), 6.74 (d, 2H, J) = 7.6 Hz), 4.56-4.67 (m, 3H), 4.23-4.42 (m, 4H), 3.58-3.63 (m, 2H), 2.93-3.19 (m, 7H), 2.39-2.43 (m, 4H), 2.11-2.16 (m, 2H), 1.99-2.06 (m, 1H), 1.78-1.91 (m, 2H), 1.60-1.65 (m, 1H), 1.27-1.45 (m, 4H); HRMS C ₄₄ H ₅₂ IN ₆ O ₁₆ (M + H) ⁺ calculated value, 1047.2484; measured value 1047.2558.

(((S) -1-carboxy-5-((S) -2-(2-(4-((S) -2-carboxy-2-((S) -4-carboxy-2-((S) -4-carboxy-2-(S) ) -4-carboxy-2- (4-iodobenzamide) butaneamide) butaneamide) ethyl) phenoxy) acetamide) -3-phenylpropanamide) pentyl) carbamoyl) -L-glutamic acid (27).
Compound 27 was prepared from 25 (29 mg, 0.019 mmol) added to 1 mL of TFA according to the same procedure described for compound 4. Compound 27: 9.7 mg (yield: 41.4%). ^{1 1} HNMR (400 MHz, MeOD) δ: 8.15 (d, 1H, J = 8.4 Hz), 7.84 (d, 2H, J = 8.4 Hz), 7.61 (d, 2H, J = 8.4 Hz), 7.14-7.28 ( m, 7H), 6.82 (d, 2H, J = 8.4 Hz), 4.62-4.68 (m, 2H), 4.39-4.55 (m, 4H), 4.31-4.32 (m, 1H), 4.23-4.24 (m, 1H), 3.06-3.20 (m, 4H), 2.92-3.02 (m, 2H), 2.33-2.45 (m, 6H), 2.03-2.15 (m, 4H), 1.86-1.93 (m, 2H), 1.74- 1.78 (m, 1H), 1.59-1.61 (m, 1H), 1.36-1.44 (m, 2H), 1.31-1.33 (m, 2H); HRMS C ₇₃ H ₁₀₇ IN ₇ O ₁₉ (M + H) ⁺ calculated value , 1535.6564; measured value 15356.6607.

The preparation of compound 29 was based on the following chemical reaction (Scheme 13).

4-(7-((5S, 8S, 11S))-5-(4-(((4S, 11S, 15S) -4-benzyl-11,15-bis (tert-butoxycarbonyl) -20,20-dimethyl) -2,5,13,18-tetraoxo-19-oxa-3,6,12,14-tetraazahenicosyl) oxy) benzyl) -8,11-bis (3- (tert-butoxy) -3- Oxopropyl) -2,2,19,19-tetramethyl-4,7,10,13,17-pentaoxo-3,18-dioxa-6,9,12-triazaikosan-16-yl) -4, 10-bis (2- (tert-butoxy) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1-yl) -5- (tert-butoxy) -5-oxopentanoic acid (28) ).
DIPEA (39 mg, 0.03 mmol), HOBt (17 mg, 0.1 mmol), EDC (19 mg, 0.1 mmol), and 1 (77 mg, 77 mg) in a solution of 21 (61 mg, 0.05 mmol) in 3 mL DMF. 0.1 mmol) was added at 0 ° C. After stirring overnight at room temperature, 20 mL of EtOAc was added to the reaction mixture. It was then washed with _H2O (10 mL x 2) and brine (10 mL), dried with _Л4 and filtered. The filtrate was concentrated and the residue was purified by FC (DCM / MeOH / NH ₄ OH = 90/9/1) to give 25 mg of 28 as a colorless oil (yield: 24.6%). HRMS C ₁₀₄ H ₁₇₀ N ₁₁ O ₂₉ (M + H) ⁺ calculated value, 2037.2166; measured value 2037.2224.

(((1S) -5-((2S) -2-(2-(4-((2S) -2-((2S) -2-((2S) -2- (4- (4,10-) Bis (carboxymethyl) -7- (1,3-dicarboxypropyl) -1,4,7,10-tetraazacyclododecane-1-yl) -4-carboxybutaneamide) -4-carboxybutaneamide)- 4-Carboxybutaneamide) -2-carboxyethyl) Phenoxy) Acetamide) -3-phenylpropanamide) -1-carboxypentyl) Carbamoyl) -L-glutamic acid (29).
Compound 29 was prepared from 28 (23 mg, 0.011 mmol) added to 1 mL of TFA according to the same procedure described for compound 4. Compound 29: 9.7 mg (yield: 59.8%). ^{1 1} HNMR (400 MHz, DMSO) δ: 8.15 (s, 1H), 8.02-8.05 (m, 3H), 7.18-7.25 (m, 5H), 6.74 (d, 2H, J = 7.6 Hz), 6.28-6.33 (m, 2H), 4.51-4.54 (m, 2H), 4.37-4.41 (m, 3H), 4.25-4.29 (m, 2H), 4.03-4.10 (m, 3H), 3.80 (s, 4H), 3.59 -3.62 (m, 4H), 2.88-3.09 (m, 18H), 2.24-2.33 (m, 8H), 1.86-1.93 (m, 6H), 1.63-1.75 (m, 6H), 1.48-1.52 (m, 2H), 1.34-1.36 (m, 2H), 1.22-1.26 (m, 2H); HRMS C ₆₄ H ₈₉ N ₁₁ O ₂₉ (M + H) ⁺ calculated value, 1476.5906; measured value 1476.5995.

The preparation of compound 38 was based on the following chemical reaction (Scheme 14).

Di-tert-butyl (((S) -6-((S) -2-(2-(4-((benzyloxy) carbonyl) phenoxy) acetamide) -3-phenylpropanamide) -1- (tert- Butoxy) -1-oxohexane-2-yl) carbamoyl) -L-glutamate (31).
Compound 31 is described for compound 28 from 10 (635 mg, 1 mmol), DIPEA (387 mg, 3 mmol), HOBt (253 mg, 1.5 mmol), EDC (285 mg, 1.5 mmol), and 30 (286 mg, 1 mmol). Prepared according to the same procedure as above. Compound 31: 672 mg (yield: 74.5%). HRMS C ₄₉ H ₆₇ N ₄ O ₁₂ (M + H) ⁺ calculated value, 903.4755, measured value 903.4789.

4-(((4S, 11S, 15S) -4-benzyl-11,15-bis (tert-butoxycarbonyl) -20,20-dimethyl-2,5,13,18-tetraoxo-19-oxa-3, 6,12,14-tetraazahenicosyl) oxy) benzoic acid (32).
A mixture of ester 31 (672 mg, 0.75 mmol) and 10% Pd / C (120 mg) added to EtOH (20 mL) was shaken with hydrogen for 3 hours. The mixture was then filtered and the filtrate was concentrated under vacuum to give 578 mg of 32 as a colorless oil (yield: 95%). HRMS C ₄₂ H ₆₁ N ₄ O ₁₂ (M + H) ⁺ calculated value, 813.4286, measured value 813.4356.
tert-Butyl N ⁶ -((benzyloxy) carbonyl) -N ² -glycyl-L-ricinate (34).

Compound 34 was added to H-Lys (Z) -OtBu (746 mg, 2 mmol), DIPEA (780 mg, 6 mmol), HOBt (506 mg, 3 mmol), EDC (570 mg, 3 mmol), piperidine (1 mL), and Fmoc-Gly-OH. Prepared from (594 mg, 2 mmol) according to the same procedure described for compound 11. Compound 34: 424 mg (yield: 54.3%). HRMS C ₂₀ H ₃₂ N ₃ O ₅ (M + H) ⁺ calculated value 394.2342, measured value 394.2392.

Tri-tert-butyl 2,2', 2''-(10-((9S) -9- (tert-butoxycarbonyl) -20,20-dimethyl-3,11,14,18-tetraoxo-1-phenyl) -2,19-dioxa-4,10,13-triazahenicosan-17-yl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate (35).
Compound 35 was added to DOTAG A-tetra (t-Bu ester) (140 mg, 0.2 mmol), DIPEA (78 mg, 0.6 mmol), HOBt (51 mg, 0.3 mmol), EDC (57 mg, 0.3 mmol), and 34. Prepared from (79 mg, 0.2 mmol) according to the same procedure described for compound 28. Compound 35: 103 mg (yield: 50.1%). HRMS C ₅₅ H ₉₄ N ₇ O ₁₄ (M + H) ⁺ calculated value, 1076.6859, measured value 1076.6938.

Tri-tert-butyl 2,2', 2''-(10-((5S) -5- (4-aminobutyl) -2,2,16,16-tetramethyl-4,7,10,14-" Tetraoxo-3,15-dioxa-6,9-diazaheptadecane-13-yl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate (36).
Compound 36 was prepared from 35 (100 mg, 0.1 mmol), and Pd / C (20 mg) according to the same procedure described for compound 32. Compound 36: 83.7 mg (yield: 89.0%). HRMS C ₄₇ H ₈₈ N ₇ O ₁₂ (M + H) ⁺ calculated value, 942.6491, measured value 942.6583.

Di-tert-butyl (((2S) -1- (tert-butoxy) -6-((2S) -2-(2-(4-(((5S) -6- (tert-butoxy) -5-) (2- (5- (tert-butoxy) -5-oxo-4- (4,7,10-tris (2- (tert-butoxy) -2-oxoethyl) -1,4,7,10-tetraaza) Cyclododecane-1-yl) pentanamide) acetamide) -6-oxohexyl) carbamoyl) phenoxy) acetamide) -3-phenylpropanamide) -1-oxohexane-2-yl) carbamoyl) -L-glutamate (37) ..
Compound 37 was added to 36 (40 mg, 0.042 mmol), DIPEA (16.2 mg, 0.126 mmol), HOBt (11 mg, 0.063 mmol), EDC (12 mg, 0.063 mmol), and 32 (34 mg, 0.2 mmol). ), Prepared according to the same procedure described for compound 28. Compound 37: 21 mg (yield: 28.8%). HRMS C ₈₉ H ₁₄₆ N ₁₁ O ₂₃ (M + H) ⁺ calculated value, 1737.0593, measured value 1737.0675.
(((1S) -1-carboxy-5-((2S) -2-(2-(4-(((5S) -5-carboxy-5- (2- (4-carboxy-4- (4)) 7,10-Tris (carboxymethyl) -1,4,7,10-tetraazacyclododecane-1-yl) butaneamide) acetamide) pentyl) carbamoyl) phenoxy) acetamide) -3-phenylpropanamide) pentyl) carbamoyl) -L-Glutamic acid (38).

Compound 38 was prepared from the addition of 37 (20 mg, 0.011 mmol) to 1 mL of TFA according to the same procedure described for compound 4. Compound 38: 6.8 mg (yield: 48.0%). HRMS C ₅₇ H ₈₂ N ₁₁ O ₂₃ (M + H) ⁺ calculated value, 1288.5585; measured value 1476.5995.

The preparation of compound 42 was based on the following chemical reaction (Scheme 15).

Benzyl (2-((bis (diethoxyphosphoryl) methyl) amino) -2-oxoethyl) carbamate (39).
Compound 39 was added to Z-Gly (209 mg, 1 mmol), DIPEA (387 mg, 3 mmol), HOBt (253 mg, 1.5 mmol), EDC (285 mg, 1.5 mmol), and tetraethyl (aminomethylene) bis (phosphonate) (303 mg). From 1 mmol), prepared according to the same procedure described for compound 28. Compound 39: 150 mg (yield: 30.4%). HRMS C ₁₉ H ₃₃ N ₂ O ₉ P ₂ (M + H) ⁺ calculated value 495.1661, measured value 495.1679.

Tetraethyl ((2-aminoacetamide) methylene) bis (phosphonate) (40).
Compound 40 was prepared from 39 (1 g, 2 mmol), and Pd / C (200 mg) according to the same procedure described for compound 32. Compound 40: 525 mg (yield: 72.9%). HRMS C ₁₁ H ₂₇ N ₂ O ₇ P ₂ (M + H) ⁺ calculated value, 361.1293, measured value 361.1342.
Di-tert-butyl (((2S) -6-((2S) -2-(2-(4-((2R) -2- (2- (4- (7- (5-((2-() (Bis (diethoxyphosphoryl) methyl) amino) -2-oxoethyl) amino) -1- (tert-butoxy) -1,5-dioxopentan-2-yl) -4,10-bis (2- (tert-tert) -Butoxy) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1-yl) -5- (tert-butoxy) -5-oxopentanamide) acetamide) -3- (tert-butoxy) ) -3-oxopropyl) phenoxy) acetamide) -3- (naphthalen-2-yl) propanamide) -1- (tert-butoxy) -1-oxohexane-2-yl) carbamoyl) -L-glutamate (41) ).

Compound 41, 40 (13.7 mg, 0.038 mmol), DIPEA (14.7 mg, 0.114 mmol), HOBt (9.6 mg, 0.057 mmol), EDC (10.8 mg, 0.057 mmol), and 3 Prepared from (65 mg, 0.038 mmol) according to the same procedure described for compound 28. Compound 41: 44 mg (yield: 56.1%). HRMS C ₉₉ H ₁₆₇ N ₁₂ O ₃₀ P ₂ (M + H) ⁺ calculated value, 2066.1386, measured value 2066.1480.

(((1S) -1-carboxy-5-((2S) -2-(2-(4-((2R) -2-carboxy-2- (2- (4-carboxy-4- (7- (7-) 1-carboxy-4-((2-((diphosphonomethyl) amino) -2-oxoethyl) amino) -4-oxobutyl) -4,10-bis (carboxymethyl) -1,4,7,10-tetraazacyclo Dodecane-1-yl) Butanamide) Acetamide) Ethyl) Phenoxy) Acetamide) -3-Phenylpropanamide) Pentyl) Carbamic acid) -L-glutamic acid (42).
1 mL of TMSBr was added at 0 ° C. to a solution of 41 (42 mg, 0.02 mmol) in 1 mL of DMF. The mixture was slowly warmed to room temperature, stirred overnight and the solvent was evacuated. The residue was treated with 1 mL of TFA. After stirring at room temperature for 5 hours, the solvent was removed and the residue was purified by half-taken HPLC to give 12 mg of 42 as a white solid (yield: 39.9%). ¹ HNMR (400 MHz, DMSO) δ: 7.16-7.24 (m, 5H), 7.09 (d, 2H, J = 8.4 Hz), 6.73 (d, 2H, J = 8.4 Hz), 4.49-4.53 (m, 1H) ), 4.36-4.42 (m, 4H), 4.07-4.10 (m, 1H), 4.00-4.04 (m, 1H), 3.68-3.83 (m, 8H), 3.29-3.39 (m, 2H), 3.17-3.28 (m, 2H), 2.94-3.09 (m, 12H), 2.79-2.88 (m, 6H), 2.22-2.34 (m, 6H), 1.88-1.94 (m, 2H), 1.64-1.74 (m, 2H) , 1.49-1.54 (m, 1H), 1.32-1.36 (m, 2H), 1.17-1.24 (m, 2H); HRMS C ₅₉ H ₈₈ N ₁₂ O ₃₀ P ₂ (M + 2H) ²⁺ calculated value, 753.2597 , Measured value 753.2769.

The preparation of compound 51 was based on the following chemical reaction (Scheme 16).

Methyl ((benzyloxy) carbonyl) glycyl-L-tyrosinate (43).
Compound 43 was added to Z-Gly (1.045 g, 5 mmol), DIPEA (1.94 g, 15 mmol), HOBt (1.26 g, 7.5 mmol), EDC (1.42 g, 7.5 mmol), and Methyl L-. Prepared from tyrosinate (975 mg, 5 mmol) according to the same procedure described for compound 28. Compound 43: 760 mg (yield: 50.5%). HRMS C ₂₀ H ₂₃ N ₂ O ₆ (M + H) ⁺ calculated value, 387.1556, measured value 387.1579.
Methyl (S) -2- (2-(((benzyloxy) carbonyl) amino) acetamide) -3-(4- (2- (tert-butoxy) -2-oxoethoxy) phenyl) propanoate (44).

To a solution of 43 (760 mg, 2 mmol) in 20 mL ACN was added t-butyl bromoacetate (390 mg, ₂ mmol) and K2 CO ₃ (552 mg, 4 mmol). The mixture was then stirred at room temperature for 3 hours and filtered. The filtrate was concentrated and the residue was purified by FC (EtOAc / Hexanes = 1/1) to give 44 as a colorless oil (yield: 770 mg, 77%). HRMS C ₂₆ H ₃₃ N ₂ O ₈ (M + H) ⁺ calculated value: 501.237, measured value 501.2143.

(S) -2- (2-(((benzyloxy) carbonyl) amino) acetamide) -3-(4- (2- (tert-butoxy) -2-oxoethoxy) phenyl) propionic acid (45).
A solution of 44 (770 mg, 1.54 mmol) in 20 mL of MeOH / NaOH (1N) (1/1) was stirred at room temperature for 2 hours. Hydrochloric acid (1N) was then added to the reaction mixture to pH = 4-5. The resulting mixture was extracted with EtOAc (50 mL x 3). The organic layer was then dried on י ₄ and filtered. The filtrate was concentrated and the residue was purified by FC (DCM / MeOH / NH ₄ OH = 90/9/1) to give 45 as a white solid (yield: 560 mg, 74.8%). HRMS C ₂₅ H ₃₁ N ₂ O ₈ (M + H) ⁺ calculated value: 487.2080, measured value 487.1997.

tert-butyl (S) -2-(4-(2-(2-(((benzyloxy) carbonyl) amino) acetamide) -3-((2-((bis (diethoxyphosphoryl) methyl) amino)-)- 2-oxoethyl) amino) -3-oxopropyl) phenoxy) acetate (46).
Compound 46 from 45 (560 mg, 1.15 mmol), DIPEA (451 mg, 3.5 mmol), HOBt (291 mg, 1.73 mmol), EDC (328 mg, 1.73 mmol), and 40 (400 mg, 1.11 mmol). , Prepared according to the same procedure described for compound 28. Compound 46: 760 mg (yield: 79.8%). HRMS C ₃₆ H ₅₅ N ₄ O ₁₄ P ₂ (M + H) ⁺ calculated value, 829.3190, measured value 829.3320.

(S) -2- (4- (2- (2-(((benzyloxy) carbonyl) amino) acetamide) -3-((2-((bis (diethoxyphosphoryl) methyl) amino) -2-oxoethyl) ) Amino) -3-oxopropyl) phenoxy) acetic acid (47).
A solution of 46 (760 mg, 0.92 mmol) in 10 mL of TFA was stirred at room temperature for 5 hours. The solvent was removed and the residue was purified with FC (EtOAc) to give 47 as a colorless oil (yield: 320 mg, 45.1%). HRMS C ₃₂ H ₄₇ N ₄ O ₁₄ P ₂ (M + H) ⁺ calculated value: 773.2564, measured value 773.2652.

Di-tert-butyl (((S) -6-((S) -2-(2-(4-((S) -2-(2-(((benzyloxy) carbonyl) amino) acetamide) -3) -3 -((2-((Bis (diethoxyphosphoryl) methyl) amino) -2-oxoethyl) amino) -3-oxopropyl) phenoxy) acetamide) -3-phenylpropanamide) -1- (tert-butoxy)- 1-oxohexane-2-yl) carbamoyl) -L-glutamate (48).
Compound 48 from 47 (320 mg, 0.415 mmol), DIPEA (155 mg, 1.2 mmol), HOBt (100 mg, 0.6 mmol), EDC (114 mg, 0.6 mmol), and 10 (261 mg, 0.415 mmol). , Prepared according to the same procedure described for compound 28. Compound 48: 310 mg (yield: 53.8%). HRMS C ₆₅ H ₉₉ N ₈ O ₂₁ P ₂ (M + H) ⁺ calculated value, 1389.6400, measured value 1389.6318.

Di-tert-butyl (((S) -6-((S) -2-(2-(4-((S) -2- (2-aminoacetamide) -3-((2-((bis (bis) Diethoxyphosphoryl) methyl) amino) -2-oxoethyl) amino) -3-oxopropyl) phenoxy) acetamide) -3-phenylpropanamide) -1- (tert-butoxy) -1-oxohexane-2-yl) Carbamoyl) -L-glutamate (49).
Compound 49 was prepared from 48 (310 mg, 0.22 mmol), and Pd / C (60 mg) according to the same procedure described for compound 32. Compound 49: 250 mg (yield: 90.6%). HRMS C ₅₇ H ₉₃ N ₈ O ₁₉ P ₂ (M + H) ⁺ calculated value, 1255.6032, measured value 1255.6122.

Di-tert-butyl (((2S) -6-((2S) -2-(2-(4-((2S) -3-((2-((bis (diethoxyphosphoryl) methyl) amino)-)- 2-oxoethyl) amino) -2- (2- (5- (tert-butoxy) -5-oxo-4- (4,7,10-tris (2- (tert-butoxy) -2-oxoethyl) -1) -1 , 4,7,10-Tetraazacyclododecane-1-yl) pentanamide) acetamide) -3-oxopropyl) phenoxy) acetamide) -3-phenylpropanamide) -1- (tert-butoxy) -1-oxo Hexane-2-yl) carbamoyl) -L-glutamate (50).
Compound 50 was added to 49 (230 mg, 0.183 mmol), DIPEA (58 mg, 0.45 mmol), HOBt (38 mg, 0.225 mmol), EDC (43 mg, 0.225 mmol), and DOTAG A-tetra (t-Bu ester). Prepared from (107 mg, 0.152 mmol) according to the same procedure described for compound 28. Compound 50: 58 mg (yield: 19.7%). HRMS C ₉₂ H ₁₅₅ N ₁₂ O ₂₈ P ₂ (M + H) ⁺ calculated value, 1938.0549, measured value 1938.0721.

(((1S) -1-carboxy-5-((2S) -2-(2-(4-((2S) -2-(2- (4-carboxy-4- (4,7,10-tris) (Carboxymethyl) -1,4,7,10-tetraazacyclododecane-1-yl) butaneamide) acetamide) -3-((2-((diphosphonomethyl) amino) -2-oxoethyl) amino) -3-oxo Propyl) phenoxy) acetamide) -3-phenylpropanamide) pentyl) carbamoyl) -L-glutamic acid (51).
Compound 51 was prepared from 50 (50 mg, 0.026 mmol), TMSBr (1 mL), DMF (1 mL), and TFA (1 mL) according to the same procedure described for compound 42. Compound 51: 12 mg (yield: 32.2%). ^{1 1} HNMR (400 MHz, DMSO) δ: 7.13-7.27 (m, 5H), 6.74 (d, 2H, J = 8.4 Hz), 6.28-6.34 (m, 3H), 4.45-4.57 (m, 5H), 4.04 -4.11 (m, 2H), 3.74-3.94 (m, 6H), 3.48-3.61 (m, 6H), 3.30-3.32 (m, 2H), 2.84-3.10 (m, 12H), 2.72-2.74 (m, 2H), 2.45-2.47 (m, 4H), 2.22-2.28 (m, 2H), 1.88-1.97 (m, 2H), 1.64-1.74 (m, 2H), 1.49-1.53 (m, 1H), 1.33- 1.38 (m, 2H), 1.25-1.29 (m, 2H); HRMS C ₅₆ H ₈₁ N ₁₂ O ₂₈ P ₂ (MH) ^-calculated value, 1431.4764; measured value 1431.4543.

(4S, 11S, 15S) -4-benzyl-1- (4-((2S) -2- (2- (4- (4,10-bis (carboxymethyl) -7- (1,3-dicarboxy)) Propyl) -1,4,7,10-tetraazacyclododecane-1-yl) -4-carboxylatebutaneamide) acetamide) -2-carboxyethyl) phenoxy) -2,5,13-trioxo-3,6 , 12,14-Tetraazaheptadecane-11,15,17-tricarboxylate gallium ([ ^nat Ga] 4).
60 μL of GaCl3 solution (1.13M) was added to a solution of compound 4 (30 mg, 0.0235 mmol) in 1 mL of H2O. The pH was adjusted to 4-5 by adding 1N HCl and the mixture was stirred at 80 ° C. for 1 hour and then purified by half-take HPLC. The solvent was removed under vacuum to give a 6.8 mg white solid. HRMS C ₅₆ H ₇₆ GaN ₁₀ O ₂₄ (M + H) + calculated value: 1341.4290, measured value 1341.4325.

(4S, 11S, 15S) -4-benzyl-1- (4-((2S) -2- (2- (4- (4,10-bis (carboxymethyl) -7- (1,3-dicarboxy)) Propyl) -1,4,7,10-tetraazacyclododecane-1-yl) -4-carboxylatebutaneamide) acetamide) -2-carboxyethyl) phenoxy) -2,5,13-trioxo-3,6 , 12,14-Tetraazaheptadecane-11,15,17-tricarboxylate lutetium ([ ^nat Lu] 4).
A solution of LuCl3 (0.25M) in 100 μL of 0.1N HCl was added to compound 4 (20 mg, 15.7 μmol) added to 1 mL of HEPES (0.5 M, pH 5). The mixture was stirred at 98 ° C. for 10 minutes and then purified by half-taken HPLC. The solvent was removed under vacuum to give a 15 mg white solid. HRMS C ₅₆ H ₇₆ LuN ₁₀ O ₂₄ (M + H) + calculated value: 1487.4442, measured value 1487.4527.

(Example 6)
Evaluation of PSMA binding affinity-IC50 An in vitro binding assay was performed to determine the PSMA binding affinity of various compounds. By incubating PSMA-positive cells with any of the following: 1) 0.2 nM [ ⁶⁸ Ga] PSMA-11 or [ ¹²⁵ I] MIP-1095 as the ligand in the presence of 10 different concentrations of competing ligand. By incubating with LNCaP having; non-specific binding is defined with 20 μM 2-PMPA (2- (phosphonomethyl) ^{pentandiic acid); or 2) different concentrations of test compound (10-5-10-10 nM} , By incubating with PC-3 PIP cells having [ ¹²⁵ I] MIP-1095 (0.18 nM, diluted in PBS) in the presence of (diluted in PBS containing 0.1% bovine serum albumin). Non-specific binding (NSB) was defined with 2 μM of the known PSMA inhibitor, PSMA-617. After incubation at 37 ° C. for 1 hour, bound and free fractions were separated by vacuum filtration through a GF / B filter using a Brandel M-24R cell collector. The filter was washed twice with cold Tris-HCl buffer (50 mM, pH = 7.4) and the radioactivity on the filter was counted with a gamma counter (Wizard ² , Perkin-Elmer) with 50% efficiency. Non-specific binding was less than 10% of total binding. Data were analyzed using GraphPad Prism 6.0 by a non-linear regression algorithm to give a half inhibition concentration (IC ₅₀ ).

The binding affinity of the test compound for PSMA is with either LNCap or PC-3 PIP cell suspension, a known radiotracer known to have high affinity and specificity for PSMA, [ ⁶⁸ Ga] PSMA- Measured by competitive binding assay using 11 or [ ¹²⁵ I] MIP-1095. The _IC50 values of the four iodinated compounds, the three DOTA, DOTAG, and DOTA (GA) 2 related compounds, and the two known PSMA inhibitors are shown in Table 1. Complexes of compound 4 as well as natural Ga and natural Lu were also tested. The results showed that all of the compounds claimed in this application exhibit excellent binding affinities showing IC50 values between 1 and 50 nM. After labeling with radioisotopes, they are expected to bind to tumor tissue that overexpresses the PSMA binding site.

(Example 7)
In vitro cell uptake [ ¹⁷⁷ Lu] 5 × 10 ⁵ cells / well were grown in 12-well plates in 1 mL of medium for 48 hours to determine cell uptake of the labeled ligand. The cells were washed twice with PBS and 900 μL of fresh medium was added. A radiolabeled ligand was added and a PSMA inhibitor (2-PMPA) was applied at a final concentration of 10 μM to determine non-specific binding. All samples were prepared in triplicate. After incubation at 37 ° C., cells were washed twice to remove unbound activity and then dissolved in 1 mL of 0.5 M NaOH. Radioactivity was measured with a gamma counter. A certain amount of the solution added to the cells was also measured as ID% for the calculation of cell uptake. All ¹⁷⁷ Lu-labeled ligands exhibited high specific uptake in the PSMA-positive cell line, PIP PC3. In particular, [ ¹⁷⁷ Lu] 4 and [ ¹⁷⁷ Lu] 51 show significantly higher uptake than the reference ligand [ ¹⁷⁷ Lu] PSMA-617, which may have excellent PSMA binding and retention. It suggests. No specific binding was observed in the PSMA negative cell line, PC3.

(Example 8)
Biodistribution of [ ⁶⁸ Ga] 4, ¹⁷⁷ Lu-labeled compounds 4 and 7 in tumor-carrying nude mice
⁶⁸ Ga Label: To 15 nmol Ligand 4 (1 mg / mL DMSO) was added 20 μL of 2.0 N NaOAc, 500 μL of ⁶⁸ Ga solution (2.25 mCi). The reaction was heated in a heating block at 90 ° C. for 10 minutes in a 3 mL sealed vial. After cooling, the sample was analyzed by HPLC (HPLC: Ecrise XDB C18 150 x 4.6 mm, gradient, 2 mL / min; A: 0.1% TFA, water; B: 0.1% TFA, in ACN: 0- 2 minutes 100% A; 2-4 minutes: 0% to 100% B; 4-9 minutes: 100% B; 9-10 minutes: 100% to 0% B). The radiochemical purity of [ ⁶⁸ Ga] 4 was> 99% RCP (FIG. 1), and the injected dose was stable at 2 hours after formulation.

For iv injection, 150 μL of labeled solution was diluted to 3 mL with saline. Mice were injected with a pharmaceutical dose of 150 μL. The injected radioactivity was 19-28 μCi and the amount of PSMA ligand was constant at 0.2 nmol / mouse.

¹⁷⁷ Lu Label: To 10 μg ligand (1 mg / mL DMSO) was added 15 μL 2.0N NaOAc, 400 μL 0.05N HCl, and 20 μL ¹⁷⁷ Lu solution (780 μCi (Capintec device 450 (read × 10))). The reaction was heated in a heating block at 95 ° C. for 1 hour in a 3 mL sealed vial. After cooling, the sample was analyzed by HPLC (HPLC: Eclipse XDB-C18 150 × 4.6 mm, gradient, 1 mL / min. A: 0.1% TFA, in water; B: 0.1% TFA, in ACN: 0-4 minutes A / B 85/15%; 4-11 minutes: 85/15 to 30/70%; 11- 14 min: 30/70% to 85/15%). The radiochemical purity of [ ¹⁷⁷ Lu] 4 (FIG. 2) and [ ¹⁷⁷ Lu] 7 is> 98% and the injected dose is post-formulation. It was stable at 48 hours.

For iv injection, 150 μL of labeled solution was diluted to 3.75 mL with saline. Mice were injected with a pharmaceutical dose of 150 μL. The injected radioactivity was 100 μCi and the amount of PSMA ligand was constant at 0.72 nmol / mouse.

Biodistribution of [ ⁶⁸ Ga] 4, [ ¹⁷⁷ Lu] 4, and [ ¹⁷⁷ Lu] 7 retains PIP PC3 (PSMA positive) and PC3 (PSMA negative) tumors on the left and right shoulders for 192 hours, respectively. Determined in nude mice (Tables 3a, 3b, and 3c). Incorporation of these radioligands into PC-3 PIP tumors showed very different kinetic profiles. [ ⁶⁸ Ga] 4 showed excellent tumor uptake suitable for PET imaging. [ ¹⁷⁷ Lu] 4 is 4 hours p. i. Showed rapid tumor accumulation, reaching 22.38 ± 3.50% dose / g. In the case of [ ¹⁷⁷ Lu] 7, such high tumor uptake (35.34 ± 12.11% dose / g) was found in 24 hours, reached the highest uptake in 48 hours, and in PIP PC3 tumors. High levels of radioactivity were retained. Uptake of both ligands, [ ¹⁷⁷ Lu] 4 and [ ¹⁷⁷ Lu] 7, in PC3 tumors (PSMA negative) was clearly even lower than in PC-3 PIP tumors (PSMA positive). [ ¹⁷⁷ Lu] 4 showed rapid clearance of radioactivity from the blood, resulting in 4 hours p. i. Later it resulted in 0.02% dose / g, whereas the clearance of [ ¹⁷⁷ Lu] 7 was slow, resulting in 12.06% dose / g at the same time. By introducing the 4- (p-iodophenyl) moiety as an albumin binder, the high blood circulation of [ ¹⁷⁷ Lu] 7 resulted in unprecedentedly higher tumor uptake and retention over time. The results suggested that [ ¹⁷⁷ Lu] 4 and [ ¹⁷⁷ Lu] 7 could be useful for radionuclide therapy for prostate tumors that overexpress the PSMA binding site.

(Example 9)
Biodistribution of ¹⁷⁷ Lu-labeled compounds 42 and 51 in tumor-carrying nude mice
¹⁷⁷ Lu Label: To 10 μg ligand (42 or 51, in 1 mg / mL DMSO), 15 μL 2.0N NaOAc, 400 μL 0.05N HCl, and 20 μL ¹⁷⁷ Lu solution (780 μCi (Capintec device 450) (reading ×). 10)) was added. The reaction was heated in a heating block at 95 ° C. for 1 hour in a 3 mL sealed vial. After cooling, the sample was analyzed by HPLC (HPLC: Ecripse XDB C18 150 × 4.6 mm, gradient, 2 mL / min; A: 0.1% TFA, water; B: 0.1% TFA, in ACN: 0- 2 minutes 100% A; 2-4 minutes: 0% to 100% B; 4-9 minutes: 100% B; 9-10 minutes: 100% to 0% B). The radiochemical purity of [ ¹⁷⁷ Lu] 42 or [ ¹⁷⁷ Lu] 51 was> 98%, and the injection dose was found to be stable 24 hours after formulation. For iv injection, 150 μL of labeled solution was diluted to 3.75 mL with saline. Mice were injected with a pharmaceutical dose of 150 μL. The injected radioactivity was 100 μCi and the amount of PSMA ligand was constant at 0.72 nmol / mouse.

Similarly, the tissue distribution of [ ¹⁷⁷ Lu] 42 and [ ¹⁷⁷ Lu] 51 was evaluated in mice carrying PIP PC3 (PSMA positive) and PC3 (PSMA negative) tumors on their left and right shoulders, respectively, for 24 hours ( Table 4). Biodistribution data suggested that both agents showed excellent PIP PC3 (PSMA positive) tumor uptake; whereas PC3 (PSMA negative) tumors showed very low uptake as expected. .. Tumor-specific uptake for [ ¹⁷⁷ Lu] 51 was higher than that observed for [ ¹⁷⁷ Lu] 42. This finding is novel and unpredictable, suggesting that the location of bisphosphonate groups can have a significant effect on in vivo biodistribution. Both agents have been found to contain bisphosphonate groups and result in high specific uptake in bone. Bone uptake was consistently higher for [ ¹⁷⁷ Lu] 51. The histological distribution of [ ¹⁷⁷ Lu] 42 and [ ¹⁷⁷ Lu] 51 allows these two agents to target PSMA-positive tumors together, presumably localized in lesions associated with metastatic tumors in bone. Suggested to get. The results of this study support the use of these dual-targeted ¹⁷⁷ Lu labeling agents for the treatment of metastatic prostate cancer.

(Example 10)
In vivo distribution of ¹²⁵ I-labeled compounds 17, 18, 26, and 27 in tumor-carrying nude mice Radioiodination and purification: 100 μg of any precursor 13, 14, 22, or 23 dissolved in 100 μL EtOH; 22 μL Na ¹²⁵ I (1033-1118 μCi, in 0.1 N NaOH), 100 μL 1N HCl, and 100 μL 3% H ₂ O ₂ were added. After 15 minutes at room temperature, the reaction was stopped by adding 150 μL of saturated NaHCO ₃ . The reaction mixture was slowly added to 1.5 mL of saturated NaHCO ₃ . The vial was rinsed with 1000 μL EtOH and the mixture was further diluted with 10 mL of water. The active sample was transferred to an activated C4 small column. The mixture was pushed through and washed twice with 3 mL of water and the product eluted with 1 mL ACN. 100 μL of DMSO was added. The mixture was concentrated to about 100 μL and purified by HPLC (Agilent Eclipse XCD C18 150 × 4.6 mm, 5 μm; 4 mL / min, gradient (ACN and water; 0-1 min (20/80), 1-16 min ( 20/80 to 100/0), 16 to 16.5 minutes (100/0 to 20/80), 16.5 to 20 minutes 20/80) (collected every minute). Blow the sample under argon. And dried again, dissolved again in 500 μL CH ₂ Cl ₂ , and 1 mL of TFA was added at room temperature. After 1 hour, the solution was blown to dry and the radioactivity was incorporated into 1 mL EtOH (10 μL saturation). Ascorbic acid / EtOH was added). The radioisotopes isolated for [ ¹²⁵ I] 17, 18, 26, and 27 were 197, 189, 600, and 197 μCi, respectively. Radiolabeled protected (radiolabeled protected). Representative photographs (FIG. 3) of HPLC profiles for radiotraces of intermediates), cold standards, and final compounds are shown for [ ¹²⁵ I] 26.

For iv injection, 150 μL of the labeled solution was diluted with saline to 3.75 mL. Mice were injected with 2-3 μCi [ ¹²⁵ I] 18, 27, 26, and 18 added to 0.15 mL saline. The injected radioactivity was 2-3 μCi.

Biodistribution studies of [ ¹²⁵ I] 18, 27, 26, and 18 in tumor-carrying nude mice evaluated their ability to localize PSMA-positive tumors (Tables 5, 6, 7, and 8). [ ¹²⁵ I] 26 and [ ¹²⁵ I] 27 containing three benzene rings in the molecule show higher uptake in PIP tumors, kidneys, and spleen compared to [ ¹²⁵ I] 17 and [ ¹²⁵ I18]. Was observed. The results suggested that compounds with higher lipophilicity exhibited stronger binding affinity for PSMA in vivo. [ ¹²⁵ I] 17 and [ ¹²⁵ I] 26 with one additional glutamate in the linker are significantly faster in PIP tumors, kidneys, and spleen compared to [ ¹²⁵ I] 18 and [ ¹²⁵ I] 27. Shown washout. Observations have shown that lipophilic and in vivo biodistribution can be engineered by adding lipophilic benzene rings or hydrophilic glutamate into the linker. Liver uptake is low, indicating that [ ¹²⁵ I] 18, 27, 26, and 18-PSMA compounds were excreted preferentially through the renal system over the hepatobiliary pathway. These new agents are valuable in radionuclide therapy when labeled with beta or alpha-releasing isotopes; however, these agents are also useful as diagnostic agents when labeled with gamma-releasing isotopes. Become.

Although specific embodiments have been exemplified and described, it should be understood that they can be modified and modified by one of ordinary skill in the art without departing from the broader aspects of the art as defined in the appended claims. be.

The disclosure is not limited to the particular embodiments described in this application. Modifications and variations can be made without departing from their spirit and scope, as will be apparent to the technician in the field. Functionally equivalent methods and compositions within the scope of the present disclosure are apparent to the technician in the art from the above description, in addition to those listed herein. Such modifications and variations shall be included in the appended claims. The present disclosure shall be limited in addition to the appended claims to the full scope of equivalents entitled by such claims. It should be understood that this disclosure is not limited to a particular method, reagent, compound composition or biological system and may of course vary. It should also be understood that the terminology used herein is for the purpose of describing only certain embodiments and not for the purpose of limiting them.

All publications, patent applications, issued patents or other documents described herein are specifically and individually incorporated by reference in their entirety by individual publications, patent applications, issued patents or other documents. Incorporated herein by reference as if indicated. Definitions contained in the text incorporated by reference are excluded to the extent that they conflict with the definitions in this disclosure.
Abbreviation:
SPECT, single photon emission tomography;
PET, Positron Emission Tomography HPLC, High Performance Liquid Chromatography;
HRMS, high resolution mass spectrometry;
PBS, Phosphate Buffered Saline;
SPE, solid phase extraction;
TFA, trifluoroacetic acid;
GMP: Good manufacturing practice;
NET: Neuroendocrine tumor FDG, 2-fluoro-2-deoxy-D-glucose DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate DOTA-TOC, DOTA-D -Phe-c (Cys-Tyr-D-Trp-Lys-Thr-Cys) -Thr-All DOTA-TATE, DOTA-D-Phe-c (Cys-Tyr-D-Trp-Lys-Thr-Cys)- Thr
DOTA-NOC, DOTA-D-Phe-c (Cys-Nal-D-Trp-Lys-Thr-Cys) -Thr-All NOTA: 1,4,7-Triazacyclononan-N, N', N' ′ -NODAGA triacetate: 1,4,7-triazacyclononane, 1-glutaric acid-4,7-DOTAGA acetate: 1,4,7,10-tetraazacyclodosecan, 1- (glutaric acid)- 4,7,10-Triacetic acid DOTA (GA) 2: 1,4,7,10-tetraazacyclodosecan, 1,7- (diglutaric acid) -4,10-diacetate TRAP: 1,4,7 -Triazacyclononan-N, N', N''-tris (methylenephosphon) acid DDPA: 1,2-[[6- (carboxy) -pyridine-2-yl] -methylamino] ethane AAZTA: 6- [Bis (hydroxycarbonyl-methyl) amino] -1,4-bis (hydroxycarbonylmethyl) -6-methylperhydro-1,4-diazepine,
EDTMP (Ethylene-Diamino-N, N, N', N'-Tetrakis-Methylene-Phosphoric Acid) Bis- (Glu-NH-CO-NH-Lys- (Ahx) -HBED-CC)
[ ¹¹ C] -MCG: [ ¹¹ C] (S) -2- [3-((R) -1-carboxy-2-methylsulfanyl-ethyl) -ureido] -pentanedioic acid,
[ ¹⁸ F] DCFBC: N- [N-[(S) -1,3-dicarboxypropyl] carbamoyl] -4- [ ¹⁸ F] -fluorobenzyl-L-cysteine,
[ ¹⁸ F] DCFPyL: 2-(3- (1-carboxy-5-[(6- [ ¹⁸ ] Fluoro-Pyridine-3-carbonyl) -Amino] -Pentyl) -Ureid) -Pentanedioic acid,
PSMA-11 Glu-NH-CO-NH-Lys- (Ahx)-(HBED-CC)
PSMA-617: 2- [3- (1-carboxy-5- (3-naphthalen-2-yl-2-] (4-([2- (4,7,10-tris-carboxymethyl-1,4) , 7,10-Tetraaza-cyclododeca-1-yl) -acetylamino] -methyl) -cyclohexanecarbonyl) -amino] -propionylamino) -pentyl) -ureido] -pentanic acid GPI 2 [(3-amino-3) -Carboxypropyl) (hydroxy) (phosphinyl) -methyl] pentane-1,5-diic acid 2-PMPA 2- (3-mercaptopropyl) pentan-diic acid References
[1] Afshar-Oromieh A, Haberkorn U, Zechmann C, Armor T, Mier W, Spohn F, et al. Repeated PSMA-targeting radioligand therapy of metastatic prostate cancer with (131) I-MIP-1095. Eur. J. Nucl. Med. Mol. Imaging 2017; 44: 950-9.
[2] Reyes DK, Demehri S, Werner RA, Pomper MG, Gorin MA, Rowe SP, et al. PSMA-targeted [(18) F] DCFPyL PET / CT-avid lesions in a patient with prostate cancer: Clinical decision- making informed by the PSMA-RADS interpretive framework. Urol Case Rep 2019; 23: 72-4.
[3] Giesel FL, Knorr K, Spohn F, Will L, Maurer T, Flechsig P, et al. Detection efficacy of [(18) F] PSMA-1007 PET / CT in 251 Patients with biochemical recurrence after radical prostatectomy. J . Nucl. Med. 2018.
[4] Fendler WP, Calais J, Eiber M, Flavell RR, Mishoe A, Feng FY, et al. Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA Oncol 2019 ..
[5] Zha Z, Ploessl K, Choi SR, Wu Z, Zhu L, and Kung HF. Synthesis and evaluation of a novel urea-based (68) Ga-complex for imaging PSMA binding in tumor. Nucl. Med. Biol. 2018; 59: 36-47.
[6] Velikyan I. 68Ga-Based Radiopharmaceuticals: Production and Application Relationship. Molecules 2015; 20: 12913-43.
[7] Banerjee S, Pillai MR, and Knapp FF. Lutetium-177 therapeutic radiopharmaceuticals: linking chemistry, radiochemistry, and practical applications. Chem. Rev. 2015; 115: 2934-74.
[8] Kostelnik TI and Orvig C. Radioactive Main Group and Rare Earth Metals for Imaging and Therapy. Chem. Rev. 2018.
[9] Ballinger JR. Theranostic radiopharmaceuticals: established agents in current use. Br. J. Radiol. 2018; 91: 20170969.
[10] Kratochwil C, Haberkorn U, and Giesel FL. Radionuclide Therapy of Metastatic Prostate Cancer. Semin. Nucl. Med .: Elsevier; 2019.
[11] Hofman MS, Hicks RJ, Maurer T, and Eiber M. Prostate-specific Membrane Antigen PET: Clinical Utility in Prostate Cancer, Normal Patterns, Pearls, and Pitfalls. Radiographics 2018; 38: 200-17.
[12] O'Keefe DS, Bacich DJ, Huang SS, and Heston WDW. A Perspective on the Evolving Story of PSMA Biology, PSMA-Based Imaging, and Endoradiotherapeutic Strategies. J. Nucl. Med. 2018; 59: 1007-13 ..
[13] Rowe SP, Gorin MA, and Pomper MG. Imaging of Prostate-Specific Membrane Antigen with Small-Molecule PET Radiotracers: From the Bench to Advanced Clinical Applications. Annu. Rev. Med. 2019; 70: 461-77.
[14] Wustemann T, Haberkorn U, Babich J, and Mier W. Targeting prostate cancer: Prostate-specific membrane antigen based diagnosis and therapy. Med. Res. Rev. 2019; 39: 40-69.
[15] Kulkarni HR, Singh A, Langbein T, Schuchardt C, Mueller D, Zhang J, et al. Theranostics of prostate cancer: from molecular imaging to precision molecular radiotherapy targeting the prostate specific membrane antigen. Br. J. Radiol. 2018 91: 20180308.
[16] Emmett L, Crumbaker M, Ho B, Willowson K, Eu P, Ratnayake L, et al. Results of a Prospective Phase 2 Pilot Trial of (177) Lu-PSMA-617 Therapy for Metastatic Castration-Resistant Prostate Cancer Including Imaging Predictors of Treatment Response and Patterns of Progression. Clin. Genitourin. Cancer 2019; 17: 15-22.
[17] Heck MM, Tauber R, Schwaiger S, Retz M, D'Alessandria C, Maurer T, et al. Treatment Outcome, Toxicity, and Predictive Factors for Radioligand Therapy with (177) Lu-PSMA-I & T in Metastatic Castration-resistant Prostate Cancer
Post-therapeutic dosimetry of 177Lu-DKFZ-PSMA-617 in the treatment of patients with metastatic castration-resistant prostate cancer. Eur. Urol. 2018; 38: 91-8.
[18] Tsionou MI, Knapp CE, Foley CA, Munteanu CR, Cakebread A, Imberti C, et al. Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling. RSC Adv 2017; 7: 49586-99.
[19] Price EW and Orvig C. Matching chelators to radiometals for radiopharmaceuticals. Chem. Soc. Rev. 2014; 43: 260-90.
[20] Stasiuk GJ and Long NJ. The ubiquitous DOTA and its derivatives: the impact of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid on biomedical imaging. Chem. Commun. (Camb. ) 2013; 49: 2732-46.
[21] Roosenburg S, Laverman P, Joosten L, Cooper MS, Kolenc-Peitl PK, Foster JM, et al. PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with (64) Cu , (68) Ga, and (111) In. Mol. Pharm. 2014; 11: 3930-7.
[22] Notni J, Simecek J, and Wester HJ. Phosphinic acid functionalized polyazacycloalkane chelators for radiodiagnostics and radiotherapeutics: unique characteristics and applications. ChemMedChem 2014; 9: 1107-15.
[23] Baum RP, Kulkarni HR, Muller D, Satz S, Danthi N, Kim YS, et al. First-In-Human Study Demonstrating Tumor-Angiogenesis by PET / CT Imaging with (68) Ga-NODAGA-THERANOST, a High-Affinity Peptidomimetic for alphavbeta3 Integrin Receptor Targeting. Cancer Biother. Radiopharm. 2015; 30: 152-9.
[24] Eisenwiener KP, Prata MI, Buschmann I, Zhang HW, Santos AC, Wenger S, et al. NODAGATOC, a new chelator-coupled somatostatin analogue labeled with [67 / 68Ga] and [111In] for SPECT, PET, and targeted therapeutic applications of somatostatin receptor (hsst2) expressing tumors. Bioconjug. Chem. 2002; 13: 530-41.
[25] Boros E, Ferreira CL, Yapp DT, Gill RK, Price EW, Adam MJ, et al. RGD conjugates of the H2dedpa scaffold: synthesis, labeling and imaging with 68Ga. Nucl. Med. Biol. 2012; 39: 785 -94.
[26] Manzoni L, Belvisi L, Arosio D, Bartolomeo MP, Bianchi A, Brioschi C, et al. Synthesis of Gd and (68) Ga complexes in conjugation with a conformationally optimized RGD sequence as potential MRI and PET tumor-imaging probes .ChemMedChem 2012; 7: 1084-93.
[27] Waldron BP, Parker D, Burchardt C, Yufit DS, Zimny M, and Roesch F. Structure and stability of hexadentate complexes of ligands based on AAZTA for efficient PET labelling with gallium-68. Chem. Commun. (Camb.) 2013; 49: 579-81.
[28] Pomper MG, Musachio JL, Zhang J, Scheffel U, Zhou Y, Hilton J, et al. 11C-MCG: synthesis, uptake selectivity, and primate PET of a probe for glutamate carboxypeptidase II (NAALADase). Mol. Imaging 2002; 1: 96-101.
[29] Rowe SP, Gage KL, Faraj SF, Macura KJ, Cornish TC, Gonzalez-Roibon N, et al. J. Nucl. Med. 2015; 56: 1003-10.
[30] Cho SY, Gage KL, Mease RC, Senthamizhchelvan S, Holt DP, Jeffrey-Kwanisai A, et al. Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer. J. Nucl. Med. 2012; 53: 1883-91.
[31] Chen Y, Pullambhatla M, Foss CA, Byun Y, Nimmagadda S, Senthamizhchelvan S, et al. 2- (3- {1-Carboxy-5-[(6- [18F] fluoro-pyridine-3-carbonyl )-amino] -pentyl} -ureido)-pen tanedioic acid, [18F] DCFPyL, a PSMA-based PET imaging agent for prostate cancer. Clin. Cancer Res. 2011; 17: 7645-53.
[32] Szabo Z, Mena E, Rowe SP, Plyku D, Nidal R, Eisenberger MA, et al. Initial Evaluation of [(18) F] DCFPyL for Prostate-Specific Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer . Mol. Imaging Biol. 2015; 17: 565-74.
[33] Eder M, Eisenhut M, Babich J, and Haberkorn U. PSMA as a target for radiolabelled small molecules. Eur. J. Nucl. Med. Mol. Imaging 2013; 40: 819-23.
[34] Eder M, Neels O, Mueller M, Bauder-Wuest U, Remde Y, Schaefer M, et al. Novel preclinical and radiopharmaceutical aspects of [68Ga] Ga-PSMA-HBED-CC: a new PET tracer for imaging of prostate cancer. Pharmaceuticals 2014; 7: 779-96.
[35] Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of Hybrid 68Ga-PSMA Ligand PET / CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J. Nucl. Med. 2015; 56: 668-74.
[36] Benesova M, Schafer M, Bauder-Wust U, Afshar-Oromieh A, Kratochwil C, Mier W, et al. Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. J. Nucl. Med. 2015; 56: 914-20.
[37] Kabasakal L, AbuQbeitah M, Aygun A, Yeyin N, Ocak M, Demirci E, et al. Pre-therapeutic dosimetry of normal organs and tissues of Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer. Eur. J. Nucl. Med. Mol. Imaging 2015.
[38] Afshar-Oromieh A, Hetzheim H, Kratochwil C, Benesova M, Eder M, Neels OC, et al. The novel theranostic PSMA-ligand PSMA-617 in the diagnosis of prostate cancer by PET / CT: biodistribution in humans, radiation dosimetry and first evaluation of tumor lesions. J. Nucl. Med. 2015; 56: 1697-705.
[39] Weineisen M, Schottelius M, Simecek J, Baum RP, Yildiz A, Beykan S, et al. 68Ga- and 177Lu-Labeled PSMA I & T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies . J. Nucl. Med. 2015; 56: 1169-76.
[40] Herrmann K, Bluemel C, Weineisen M, Schottelius M, Wester HJ, Czernin J, et al. Biodistribution and radiation dosimetry for a probe targeting prostate-specific membrane antigen for imaging and therapy. J. Nucl. Med. 2015; 56: 855-61.

Claims (40)

Formula I:

Compound, or a pharmaceutically acceptable salt thereof,
During the ceremony
Z is the chelated moiety, or Z ¹ :

It is a group having the structure of
Where Y ¹⁰ is CH or N;
Each of L and La is independently ^a bond, or a divalent link containing 1 to 6 carbon atoms in a chain, ring, or combination thereof, requiring at least one carbon atom. Replaced by O, -NR ^3- , or -C (O)-accordingly;
R ^* is a radioisotope;
R ²² is selected from the group consisting of alkyl, alkoxyl, halides, haloalkyl, and CN;
p is an integer from 0 to 4, and if p is greater than 1, each R ²² is the same or different;
W is a PSMA target ligand;
Each T ¹ is independently T ¹¹ or T ¹² :

Has the structure of
Here, R ²³ is − (CH ₂ ) _a CO ₂ H, and a is an integer from 0 to 4;
Each T ² is independently T ²¹ or T ²² :

Has the structure of
Where b is an integer from 1 to 6 and G ¹ is O, S, or NR ³ ;
q is 0, 1, 2, or 3;
r is 0, 1, or 2;
A ² is a bond, or a divalent linking moiety containing 1 to 20 carbon atoms in a chain, ring, or combination thereof, with one or more carbon atoms O, as needed. Can be replaced with -NR ⁴⁰ -or-C (O)-;
B ² is H,

And
Where c is an integer from 1 to 4 and
G is O, S, or NR ³ ;
X ² is O, S, or -NR ^41- ;
Each of R ³ , R ⁴⁰ , and R ⁴¹ is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylaryl, and heteroaryl.
R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , and R ³⁶ are each independently hydrogen, alkyl, alkoxyl, or halide;
Each of R ³⁷ and R ³⁸ is independently hydrogen, alkyl, aryl, or alkylaryl;
Each R ³⁹ is independently selected from the group consisting of alkyl, alkoxyl, halides, haloalkyl, and CN;
s is 0 or 1;
v is an integer from 0 to 4, and if v is greater than 1, each R ³⁹ is the same or different;
Where s is 1, -X ² -A ² -B ² is -OH, r is 0, q is 1, and T ¹ is T ¹¹ , then Z is Z ¹ or

A compound, or a pharmaceutically acceptable salt thereof, which is never. Z is

And
A ¹ is a bond, or a divalent linking moiety containing 1 to 20 carbon atoms in a chain, ring, or combination thereof, with one or more carbon atoms optionally O, Can be replaced with -NR ⁴⁰ -or-C (O)-;
B ¹ is H,

And
Where c is an integer from 1 to 4;
X ¹ is O, S, or -NR ^41- ;
D is a divalent chelating group derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.
The compound according to claim 1, or a pharmaceutically acceptable salt thereof. D is

The compound according to claim 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of. D is

The compound according to claim 3, or a pharmaceutically acceptable salt thereof, selected from the group consisting of. Z is the structure:

Is Z ¹ with
Where R ^* is ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ¹⁸ F, or ²¹¹ As,
The compound according to claim 1, or a pharmaceutically acceptable salt thereof. Z ¹ is the structure:

The compound according to claim 5, or a pharmaceutically acceptable salt thereof. W is the structure:

Have;
R ²⁰ and R ²¹ are independent amino acid residues, which are amino acid residues linked to an adjacent —C (O) -group via the amino group thereof.
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. W is the structure:

Have;
R ² is a hydrogen or carboxylic acid protecting group,
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. R ^37a is optionally substituted phenyl or optionally substituted naphthyl, formula IA :.

The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof. Formula IB:

9. The compound according to claim 9, or a pharmaceutically acceptable salt thereof. Formula II-A:

The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof. Equation II-B: q is 1 or 2.

The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof. Formula II-C:

The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof. Equation II-D: q is 1 or 2.

Have,
The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof. Z is

And
A ¹ is a bond, or a divalent linking moiety containing 1 to 20 carbon atoms in a chain, ring, or combination thereof, with one or more carbon atoms optionally O. , -NH-, or -C (O)-can be replaced;
B ¹ is H,

And
Here, c is 3,
X ¹ is a bond, O, or -NH-;
D is

The compound according to any one of claims 1 to 4 and 7 to 14, or a pharmaceutically acceptable salt thereof. Equation III-A:

The compound according to any one of claims 1 to 4 and 7 to 10, or a pharmaceutically acceptable salt thereof. Equation III-B:

The compound according to claim 16, or a pharmaceutically acceptable salt thereof. Equation IV-A:

The compound according to claim 17, or a pharmaceutically acceptable salt thereof. Equation IV-B:

The compound according to claim 17, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 9 to 17, wherein R ^37a is a optionally substituted phenyl. The compound according to any one of claims 2 to 4, 7 to 17, and 19 to 20, wherein X ¹ is O or -NH-, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 21, wherein X ² is bound, O, or -NH-, or a pharmaceutically acceptable salt thereof. Each of A ¹ and A ² binds,-(CH ₂ ) _n -,-(CH ₂ ) _n C (O) O-,-(CH ₂ ) _n C (O) NH-,-(CH ₂ CH). ₂ O) _n -or-(CH ₂ CH ₂ O) _n (CH ₂ CH ₂ NH) _n- ;
Each n is independently 1, 2, 3 or 4,
The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof. 23. The compound according to claim 23, wherein A ¹ is a binding,-(CH ₂ ) _n C (O) NH-, or-(CH ₂ CH ₂ O) _n (CH ₂ CH ₂ NH) _n- . Its pharmaceutically acceptable salt. The compound according to claim 24, or a pharmacy thereof, wherein A ¹ is a binding,-(CH ₂ ) C (O) NH-, or-(CH ₂ CH ₂ O) ₂ (CH ₂ CH ₂ NH)-. Acceptable salt. The compound according to any one of claims 1 to 25, wherein A ² is bound or-(CH ₂ ) _n C (O) NH-; n is 1, 2, or 3. Its pharmaceutically acceptable salt. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein A ² is bound or-(CH ₂ ) C (O) NH-. structure:

The compound according to claim 1, or a pharmaceutically acceptable salt thereof. I is radioactive, structure:

The compound according to claim 1, or a pharmaceutically acceptable salt thereof. A complex comprising the compound according to any one of claims 1 to 4 and 7 to 28 and the chelated metal M in the chelated portion of the compound, wherein M is ²²⁵ Ac, ⁴⁴ . Sc, ⁴⁷ Sc, ^203/212 Pb, ⁶⁷ Ga, ⁶⁸ Ga, ⁷² As, ^99m Tc, ¹¹¹ In, ⁹⁰ Y, ⁹⁷ Ru, ⁶² Cu, ⁶⁴ Cu, ⁵² Fe, ^52m Mn, ¹⁴⁰ La, ¹⁷⁵ Yb, ¹⁵³ A complex selected from the group consisting of Sm, ¹⁶⁶ Ho, ¹⁴⁹ Pm, ¹⁷⁷ Lu, ¹⁴² Pr, ¹⁵⁹ Gd, ²¹³ Bi, ⁶⁷ Cu, ¹¹¹ Ag, ¹⁹⁹ Au, ¹⁶¹ Tb, and ⁵¹ Cr. structure:

30. The complex of claim 30, or a pharmaceutically acceptable salt thereof. X ¹ is O or -NH-;
X ² is O or -NH-;
A ¹ is a bond,-(CH ₂ ) C (O) NH-, or-(CH ₂ CH ₂ O) ₂ (CH ₂ CH ₂ NH)-;
A ² is bound or-(CH ₂ ) C (O) NH-;
Each of B ¹ and B ² independently, H,

The complex according to claim 31, or a pharmaceutically acceptable salt thereof. The complex according to any one of claims 30 to 32, or a pharmaceutically acceptable salt thereof, wherein M is ⁶⁸ Ga or ¹⁷⁷ Lu. structure:

30. The complex of claim 30, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or complex according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof. A method for imaging in a subject
Administering the compound or complex according to any one of claims 1, 5-14, 21-27, 29, and 30-34 to the subject, and imaging the subject or part of the subject. Methods, including getting. 36. The method of claim 36, comprising obtaining an image on a device capable of detecting positron emission. Administering an effective amount of the compound or complex according to any one of claims 1, 5 to 14, 21 to 27, 29, and 30 to 34 to a subject, and a pattern of radioactivity of the complex in the subject. A method of in vivo imaging comprising detecting. An effective amount of a compound or complex according to any one of claims 1, 5 to 14, 21 to 27, 29, and 30 to 34, which is a method for treating one or more tumors of interest. To the subject. A kit comprising a sterile container containing an effective amount of the compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and instructions for use for therapeutic use.

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